Heteroaryl amidines, methylamidines and guanidines, and the use thereof as protease inhibitors

ABSTRACT

The present invention is directed to compounds of Formula I:                    
     wherein X is O, S or NR 7  and R 1 —R 7 , Y and Z are set forth in the specification, as well as hydrates, solvates or pharmaceutically acceptable salts thereof. Also described are methods for preparing the compounds of Formula I. The novel compounds of the present invention are potent inhibitors of proteases, especially trypsin-like serine proteases, such as chymotrypsin, trypsin, plasmin and urokinase. Certain of the compounds exhibit direct, selective inhibition of urokinase, or are intermediates useful for forming compounds having such activity.

This application is a continuation of U.S. Application Ser. No.09/828,783, filed Apr. 10, 2001, U.S. Pat. No. 6,403,633, which is acontinuation of U.S. Application Ser. No. 09/372,748, filed Aug. 11,1999, now U.S. Pat. No. 6,291,514, which is a continuation-in-part ofU.S. Application Ser. No. 09/247,062, filed Feb. 9, 1999, now abandoned,which application claims benefit under 35 U.S.C. §119(e) of U.S.Provisional Application No. 60/074,110, filed Feb. 9, 1998, all hereinfully incorporated by reference.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to novel heteroaryl compounds thatfunction as enzyme inhibitors, and particularly to a new class ofnon-peptidic inhibitors of proteolytic enzymes such as urokinase (uPa).

2. Related Art

Proteases are enzymes that cleave proteins at single, specific peptidebonds. Proteases can be classified into four generic classes: serine,thiol or cysteinyl, acid or aspartyl, and metalloproteases (Cuypers etal., J. Biol. Chem. 257:7086 (1982)). Proteases are essential to avariety of biological activities, such as digestion, formation anddissolution of blood clots, reproduction and the immune reaction toforeign cells and organisms. Aberrant proteolysis is associated with anumber of disease states in man and other mammals. The human neutrophilproteases, elastase and cathepsin G, have been implicated ascontributing to disease states marked by tissue destruction. Thesedisease states include emphysema, rheumatoid arthritis, corneal ulcersand glomerular nephritis. (Barret, in Enzyme Inhibitors as Drugs,Sandler, ed., University Park Press, Baltimore, (1980)). Additionalproteases such as plasmin, C-1 esterase, C-3 convertase, urokinase andtissue-type plasminogen activators, acrosin, and kallikreins play keyroles in normal biological functions of mammals. In many instances, itis beneficial to disrupt the function of one or more proteolytic enzymesin the course of therapeutically treating a mammal.

Serine proteases include such enzymes as elastase (human leukocyte),cathepsin G, plasmin, C-1 esterase, C-3 convertase, urokinase andtissue-type plasminogen activators, acrosin, chymotrypsin, trypsin,thrombin, factor Xa and kallikreins.

Human leukocyte elastase is released by polymorphonuclear leukocytes atsites of inflammation and thus is a contributing cause for a number ofdisease states. Cathepsin G is another human neutrophil serine protease.Compounds with the ability to inhibit the activity of these enzymes areexpected to have an anti-inflammatory effect useful in the treatment ofgout, rheumatoid arthritis and other inflammatory diseases, and in thetreatment of emphysema. Chymotrypsin and trypsin are digestive enzymes.Inhibitors of these enzymes are useful in treating pancreatitis.Inhibitors of urokinase plasminogen activator are useful in treatingexcessive cell growth disease states, such as benign prostatichypertrophy, prostatic carcinoma and psoriasis.

Urokinase (urinary-type plasminogen activator or uPA; InternationalUnion of Biochemistry Classification Number: EC3.4.21.31) is aproteolytic enzyme which is highly specific for a single peptide bond inplasminogen. It is a multidomain serine protease, having a catalytic “B”chain (amino acids (aa) 144-411), and an amino-terminal fragment (“ATF”,aa 1-143) consisting of a growth factor-like domain (4-43) and a Kringledomain (aa 47-135). The uPA Kringle domain appears to bind heparin, butnot fibrin, lysine, or aminohexanoic acid. The growth factor-like domainbears some similarity to the structure of epidermal growth factor (EGF)and is thus also referred to as “EGF-like” domain. The single chainpro-uPA is activated by plasmin, cleaving the chain into a two-chainactive form that is stabilized by a disulfide bond.

Cleavage of the peptide bond in plasminogen by urokinase (“plasminogenactivation”) results in the formation of a potent general protease,plasmin. Many cell types use urokinase as a key initiator ofplasmin-mediated proteolytic degradation or modification ofextracellular support structures (e.g., the extracellular matrix (ECM)and the basement membrane (BM)). Cells exist, move, and interact witheach other in tissues and organs within the physical framework providedby the ECM and BM. Movement of cells within the ECM or across the BMrequires local proteolytic degradation or modification of thesestructures, allowing cells to “invade” into adjacent areas that werepreviously unavailable.

Central to the ability of urokinase to mediate cellular migration andinvasiveness is the existence of specific high affinity urokinasereceptors (uPARs) which concentrate urokinase on the cell surface,leading to the generation of locally high plasmin concentrations betweencells and ECM or BM (Blasi, F., et al., Cell Biol. 104:801-804 (1987);Roldan, A. L., et al., EMBO J. 9:467-74 (1990)). The binding interactionis apparently mediated by the EGF-like domain (Rabbani, S. A., et al.,J. Biol. Chem. 267:14151-56 (1992)). Cleavage of pro-uPA into active uPAis accelerated when pro-uPA and plasminogen are receptor-bound. Thus,plasmin activates pro-uPA, which in turn activates more plasmin bycleaving plasminogen. This positive feedback cycle is apparently limitedto the receptor-based proteolysis on the cell surface, since a largeexcess of protease inhibitors is found in plasma, including α₂antiplasmin, PAI-1 and PAI-2. High plasmin concentrations betweeninvasive cells and ECM or BM are necessary in order to overcomeinhibitory effect of these ubiquitous plasmin inhibitors. Thus, it iscell surface receptor-bound urokinase, and not simply free urokinasesecreted by cells, which plays the predominant role in initiatingcellular invasiveness.

Plasmin can activate or degrade extracellular proteins such asfibrinogen, fibronectin, and zymogens, including matrixmetalloproteinases. Plasminogen activators thus can regulateextracellular proteolysis, fibrin clot lysis, tissue remodeling,developmental cell and smooth muscle cell migration, inflammation, andmetastasis. Cellular invasiveness initiated by urokinase is central to awide variety of normal and disease-state physiological processes(reviewed in Blasi, F., et al., J. Cell Biol. 104:801-804 (1987); Dan,K., et al., Adv. Cancer Res.44:139-266 (1985); Littlefield, B. A., Ann.N.Y. Acad. Sci. 622:167-175 (1991); Saksela, O., Biochim. Biophys. Acta823:35-65 (1985); Testa, J. E., and Quigley, J. P., Cancer Metast. Rev.9:353-367 (1990)). Such processes include, but are not limited to,angiogenesis (neovascularization), bone restructuring, embryoimplantation in the uterus, infiltration of immune cells intoinflammatory sites, ovulation, spermatogenesis, tissue remodeling duringwound repair, restenosis and organ differentiation, fibrosis, localinvasion of tumors into adjacent areas, metastatic spread of tumor cellsfrom primary to secondary sites, and tissue destruction in arthritis.Inhibitors of urokinase therefore have mechanism-based anti-angiogenic,anti-arthritic, anti-inflammatory, anti-restenotic, anti-invasive,anti-metastatic, anti-osteoporotic, anti-retinopathic (forangiogenesis-dependent retinopathies), contraceptive, and tumoristaticactivities. Inhibitors of urokinase are useful agents in the treatmentof a variety of disease states, including but not limited to, benignprostatic hypertrophy, prostatic carcinoma and psoriasis.

Beneficial effects of urokinase inhibitors have been reported usinganti-urokinase monoclonal antibodies and certain other known urokinaseinhibitors. For instance, anti-urokinase monoclonal antibodies have beenreported to block tumor cell invasiveness in vitro (Hollas, W., et al.,Cancer Res. 51:3690-3695, (1991); Meissauer, A., et al., Exp. Cell Res.192:453-459 (1991)), tumor metastasis and invasion in vivo (Ossowski,L., J. Cell Biol. 107:2437-2445 (1988); Ossowski, L., et al., J. CancerRes. 51:274-81 (199 1)), and angiogenesis in vivo (Jerdan, J. A., etal., J. Cell Biol. 115[3 Pt 2]:402a (1991)). In addition, amiloride, aknown urokinase inhibitor of only moderate potency, has been reported toinhibit tumor metastasis in vivo (Kellen, J. A., et al., Anticancer Res.8:1373-1376 (1988)) and angiogenesis/capillary network information invitro (Alliegro, M. A., et al., J. Cell Biol. 115[3 Pt 2]:402a (1991)).

Urokinase plays a significant role in vascular wound healing andarterial neointima formation after injury, most likely affectingcellular migration. Urokinase mediates plasmin proteolysis, which inturn promotes vascular wound-healing and associated neointima formation(Carmeliet et al., Circ. Res. 81:829-839 (Nov. 1997), Lupu et al.,Fibrinolysis 10 Supp 2:33-35 (1996)). A viral serine proteinaseinhibitor, SERP-1, has been employed to reduce plaque formation afterprimary balloon angioplasty in rabbits. This activity has beenattributed to the inhibition by SERP-1 of cellular proteinases, such asplasmin or urokinase (Lucas et al., Circulation 94:2890-2900 (1996)).

A need continues for non-peptidic compounds that are potent andselective urokinase inhibitors, and which possess greaterbioavailability and fewer side-effects than currently availableurokinase inhibitors. Accordingly, new classes of potent urokinaseinhibitors, characterized by potent inhibitory capacity and lowtoxicity, are potentially valuable therapeutic agents for a variety ofconditions.

SUMMARY OF THE INVENTION

The present invention is broadly directed to the use of heteroarylamidines, methylamidines and guanidines having Formula I (below) asprotease inhibitors, preferably as urokinase inhibitors.

Compounds of the present invention exhibit anti-urokinase activity viadirect, selective inhibition of urokinase, or are intermediates usefulfor forming compounds having such activity. Compounds of the presentinvention inhibit urokinase and are, therefore, useful anti-angiogenic,anti-arthritic, anti-inflammatory, anti-restenotic, anti-invasive,anti-metastatic, anti-osteoporotic, anti-retinopathic (forangiogenesis-dependent retinopathies), contraceptive, and tumoristatictreatment agents. For example, such treatment agents are useful in thetreatment of a variety of disease states, including but not limited to,benign prostatic hypertrophy, prostatic carcinoma, tumor metastasis andpsoriasis.

Also provided are methods to inhibit extracellular proteolysis, methodsto treat benign prostatic hypertrophy, prostatic carcinoma, tumormetastasis, psoriasis, and other conditions by administering thecompound of Formula I.

A number of the heteroaryl compounds described herein are novelcompounds. Therefore, the present invention is also directed to novelcompounds of Formula I.

Further provided are pharmaceutical compositions comprising a compoundof Formula I and one or more pharmaceutically acceptable carriers ordiluents and said pharmaceutical compositions further comprising athrombolytic agent such as tissue plasminogen activator andstreptokinase.

Further provided are methods of synthesizing compounds of Formula I.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The present invention is broadly directed to a method of inhibitingproteases, particularly serine proteases, by contacting a serineprotease with a compound of the general Formula I:

or a solvate, hydrate or pharmaceutically acceptable salt thereof;wherein:

X is O, S or NR⁷, where R⁷ is hydrogen, alkyl, aralkyl,hydroxy(C₂₋₄)alkyl, or alkoxy(C₂₋₄)alkyl;

Y is a direct covalent bond, CH₂ or NH;

Z is NR⁵R⁶, hydrogen or alkyl, provided that Y is NH whenever Z ishydrogen or alkyl;

R¹ is hydrogen, amino, hydroxy, halogen, cyano, C₁₋₄alkyl or —CH₂R,where R is hydroxy, amino or C₁₋₃alkoxy;

R² and R³ are independently:

i. hydrogen;

ii. halogen;

iii. hydroxy;

iv. nitro;

v. cyano;

vi. amino, monoalkylamino, dialkylamino, monoarylamino, diarylamino,monoalkylmonoarylamino, monoaralkylamino, diaralkylamino,monoalkylmonoaralkylamino, monoheterocycleamino, diheterocycleamino,monoalkylmonoheterocycleamino, alkoxycarbonylamino,aralkoxycarbonylamino, aryloxycarbonylamino, alkylsulfonylamino,aralkylsulfonylamino, aralkenylsulfonylamino, arylsulfonylamino,heteroarylsulfonylamino, di(aralkylsulfonyl)amino,di(aralkenylsulfonyl)anmino, di(arylsulfonyl)amino, ordi-(heteroarylsulfonyl)amino, formylamino, alkanoylanmino,alkenoylamino, alkynoylamino, aroylamino, aralkanoylamino,aralkenoylamino, heteroaroylamino, heteroaralkanoylamino, H(S)CNH—, orthioacylamino, wherein any of the aryl or heteroaryl containing groupscan be optionally substituted on the aromatic ring and wherein any ofthe heterocycle containing groups can be optionally ring substituted;

vii. aminocarbonyl, monoalkylaminocarbonyl, dialkylaminocarbonyl, acyl,aminoacyl, monoarylaminocarbonyl, diarylaminocarbonyl ormonoalkylmonoarylaminocarbonyl;

viii. aminothiocarbonyl, monoalkylaminothiocarbonyl,dialkylaminothiocarbonyl, thioacyl or aminothioacyl;

ix. aminocarbonylamino, mono- and dialkylaminocarbonylamino, mono- anddiarylaminocarbonylamino, or mono- and diaralkylaminocarbonylamino;

x. aminocarbonyloxy, mono- and dialkylaminocarbonyloxy, mono- anddiarylaminocarbonyloxy, mono- and diaralkylaminocarbonyloxy;

xi. aminosulfonyl, mono- and dialkylaminosulfonyl, mono- anddiarylaminosulfonyl, or mono- and diaralkylaminosulfonyl;

xii. alkoxy, or alkylthio, wherein the alkyl portion of each group maybe optionally substituted,

xiii. aralkoxy, aryloxy, heteroaryloxy, aralkylthio, arylthio, orheteroarylthio, wherein the aryl portion of each group can be optionallysubstituted;

xiv. alkylsulfonyl, wherein the alkyl portion can be optionallysubstituted;

xv. aralkylsulfonyl, aralkenylsulfonyl, arylsulfonyl orheteroarylsulfonyl, wherein the aryl portion of each group can beoptionally substituted;

xvi. alkenyl, or alkynyl;

xvii. optionally substituted aryl;

xviii. optionally substituted alkyl;

xix. optionally substituted aralkyl;

xx. optionally substituted heterocycle; or

xxi. optionally substituted cycloalkyl; and

R⁴, R⁵ and R⁶are independently hydrogen, C₁₋₄alkyl, aryl, hydroxyalkyl,aminoalkyl, monoalkylamino(C₂₋₁₀)alkyl, dialkylamino(C₂₋₁₀)alkyl,carboxyalkyl, cyano, amino, alkoxy, or hydroxy, or —CO₂R^(w), where

R^(w) is alkyl, cycloalkyl, phenyl, benzyl,

where R^(d) and R^(e) are independently hydrogen, C₁₋₆alkyl, C₂₋₆alkenylor phenyl, R^(f) is hydrogen, C₁₋₆alkyl, C₂₋₆alkenyl or phenyl, R^(g) ishydrogen, C₁₋₆alkyl, C₂₋₆alkenyl or phenyl, and R^(h) is aralkyl orC₁₋₆alkyl.

The present invention is also directed to novel compounds of Formula I,where X, Y and R¹-R⁶ are as defined above; provided that at least one ofR² or R³ is selected from the group consisting of:

(a) an optionally substituted alkyl group, preferably C₁-C₆alkyl, morepreferably C₁-C₃;

(b) alkoxy, aryloxy, alkylthio or arylthio, any of which is optionallysubstituted;

(c) optionally substituted C₆-C₁₄aryl, or optionally substitutedaralkyl, except that R³ is not nitrophenyl or aminophenyl, when R¹ andR² are both hydrogen or methyl;

(d) optionally substituted heterocycle; and

(e) optionally substituted cycloalkyl.

When an alkyl-containing group, heterocyclic-containing group oraryl-containing group of R² or R³ is optionally substituted, theoptional substituents can be 1 to 4 non-hydrogen substituents, providedthat the resulting compound is stable. Values of optional substituentson alkyl groups are halogen, hydroxy, thiol, amino, monoalkylamino,dialkylamino, formylamino, aminoiminomethyl, acylamino, aminoacyl, mono-or di-alkylaminocarbonyl, thiocarbonylamino, thioacylamino,aminothiocarbonyl, alkoxy, aryloxy, aminocarbonyloxy, mono- ordi-alkylaminocarbonyloxy, mono- or diarylaminocarbonyloxy, mono- ordiaralkylaminocarbonyloxy, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl,alkylsulfonylamino, arylsulfonylamino, aralkylsulfonyl amino,alkoxycarbonylamino, aralkoxycarbonylamino, aryloxycarbonylamino, mono-or di-alkylaminothiocarbonyl, aralkoxy, carboxy, carboxyalkyl,alkoxycarbonyl, alkoxycarbonylalkyl, nitro, cyano, trifluoromethyl,alkylthio and arylthio.

Preferred values of optional substituents on an alkyl group are chloro,hydroxy, amino, mono(C₁₋₄)alkylamino, di(C₁₋₄)alkylamino, formylamino,C₂₋₆acylamino, aminocarbonyl, C₂₋₈aminoacyl, C₁₋₆alkoxy, C₆₋₁₄aryloxy,carboxy, carboxy(C₁₋₆)alkyl, C₂₋₈alkoxycarbonyl, nitro, cyano,trifluoromethyl, C₁₋₆alkylthio, C₆₋₁₄arylthio, C₁₋₆alkylsulfonylamino,C₇₋₁₅aralkylsulfonylamino, C₆₋₁₀arylsulfonylamino, mono- ordi(C₁₋₆)alkylaminocarbonyloxy, mono- or di-(C₆₋₁₀)arylaminocarbonyloxy,mono- or di(C₇₋₁₅)aralkylcarbonytoxy, C₁₋₆alkoxycarbonylamino,C₇-C₁₅aralkoxycarbonylamino, and C₆-C₁₀aryloxycarbonylamino.

Preferred values of optional substituents on aryl-containing andheterocyclic-containing groups include chloro, hydroxy, amino,mono(C₁₋₄)alkylamino, di(C₁₋₄)alkylamino, formylamino, C₂₋₈acylamino,aminocarbonyl, C₂₋₈aminoacyl, C₃₋₇cycloalkyl, C₁₋₆alkyl, C₁₋₆alkoxy,C₆₋₁₄aryloxy, carboxy, carboxy(C₁₋₆)alkyl, C₂₋₈alkoxycarbonyl, nitro,cyano, trifluoromethyl, C₁₋₆alkylthio, C₆₋₁₄arylthio, C₆₋₁₄aryl,substituted phenyl, tetrazolyl, thienyl (further optionally substitutedby one, two or three of chloro, hydroxy, C₁₋₄alkyl, C₁₋₄alkoxy, amino orcarboxy), 3,4-methylenedioxy, 3,4-ethylenedioxy, 3,4-propylenedioxy,C₁₋₆alkylsulfonylamino, C₇₋₁₅aralkylsulfonylamino,C₁₋₆arylsulfonylamino, C₁₋₆alkyl/sulfonyl, C₆₋₁₀arylsulfonyl, mono- ordi(C₁₋₆)alkylaminocarbonyloxy, mono- or di- C₆₋₁₀arylaminocarbonyloxy,mono- or di-(C₇₋₁₅)aralkylcarbonyloxy, C₁₋₆alkoxycarbonylamino,C₇-C₁₅aralkoxycarbonylamino, C₆-C₁₀aryloxycarbonylamino,C₂₋₆thioacylamino, aminothiocarbonyl, and C₂₋₈aminothioacyl.

Preferred values of R¹ include hydrogen, amino, hydroxy and fluoro.

A preferred value of R² is Formula II:

where Ar is phenyl, thiazolyl, thiazolinyl, oxazolyl, isothiazolyl,isoxazolyl, imidazolyl, pyridyl, pyrimidinyl, pyrazinyl, thienyl(thiophenyl), pyrrolyl, oxazolinyl and benzothienyl.

Preferred values of R³ include C₁₋₄alkyl (optionally substituted),halogen, amino, acylamino, C₁₋₆alkylthio (such as methylthio orethylthio), C₁₋₆alkoxy (such as methoxy and ethoxy), trifluoromethyl,methylsulfonyl, and benzylthio.

A preferred value of X is divalent sulfur (S).

Preferred values of Y are a covalent bond or —NH—, most preferably acovalent bond.

Preferred values of R⁴, R⁵ and R⁶ in Formula I are hydrogen, hydroxy,cyano, C₁₋₆ alkyl, or C₁₋₆ alkoxy. Suitable values of R⁴, R⁵ and R⁶include hydrogen, methyl, ethyl, propyl, n-butyl, hydroxy, methoxy, andethoxy. In the most preferred embodiments, R⁴, R⁵ and R⁶ are eachhydrogen.

Preferred values of R⁴, R⁵ and R⁶ in Formula I also include prodrugssuch as —CO₂R^(w), where R^(w), in each instance, is preferably one ofC₁₋₄alkyl, C₄₋₇cycloalkyl or benzyloxycarbonyl. Suitable values of R⁴,R⁵ and R⁶ include hydrogen, methyl, ethyl, propyl, n-butyl, hydroxy,methoxy, ethoxy, cyano, —CO₂CH₃, —CO₂CH₂CH₃ and —CO₂CH₂CH₂CH₃. In themost preferred embodiments, R⁴, R⁵ and R⁶ are each hydrogen.

Also preferred at R⁴, R⁵ and R⁶ is the group —CO₂R^(w), where R^(w) isone of

where R^(d)-R^(h) are defined as above. When R⁴, R⁵ and R⁶ are—CO₂R^(w), where R^(w) is one of one of these moieties, the resultingcompounds are prodrugs that possess desirable formulation andbioavailability characteristics. A preferred value for each of R^(d),R^(c) and R^(g) is hydrogen, R^(f) is methyl, and preferred values forR^(h) include benzyl and tert-butyl.

Preferred values of R⁷ include hydrogen, C₁₋₆alkyl, C₆₋₁₀ar(C₁₋₄)alkyl,and C₂₋₆hydroxyalkyl. Suitable values are hydrogen, methyl, ethyl, andbenzyl.

The term “alkyl” as employed herein by itself or as part of anothergroup refers to both straight and branched chain radicals of up to 12carbons, such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl,isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl,2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl.

The term “alkenyl” is used herein to mean a straight or branched chainradical of 2-20 carbon atoms, unless the chain length is limitedthereto, including, but not limited to, ethenyl, 1-propenyl, 2-propenyl,2-methyl-1-propenyl, 1-butenyl, 2-butenyl, and the like. Preferably, thealkenyl chain is 2 to 10 carbon atoms in length, more preferably, 2 to 8carbon atoms in length most preferably from 2 to 4 carbon atoms inlength.

The term “alkynyl” is used herein to mean a straight or branched chainradical of 2-20 carbon atoms, unless the chain length is limitedthereto, wherein there is at least one triple bond between two of thecarbon atoms in the chain, including, but not limited to, acetylene,1-propylene, 2-propylene, and the like. Preferably, the alkynyl chain is2 to 10 carbon atoms in length, more preferably, 2 to 8 carbon atoms inlength, most preferably from 2 to 4 carbon atoms in length.

In all instances herein where there is an alkenyl or alkynyl moiety as asubstituent group, the unsaturated linkage, i.e., the vinylene oracetylene linkage is preferably not directly attached to a nitrogen,oxygen or sulfur moiety.

The term “alkylthio” as employed herein by itself or as part of anothergroup refers to a straight or branched chain radical of 1 to 20 carbonatoms, unless the chain length is limited thereto, bonded to a sulfuratom, including, but not limited to, methylthio, ethylthio,n-propylthio, isopropylthio, and the like. Preferably the alkylthiochain is 1 to 10 carbon atoms in length, more preferably 1 to 8 carbonatoms in length.

The term “alkoxy” as employed herein by itself or as part of anothergroup refers to a straight or branched chain radical of 1 to 20 carbonatoms, unless the chain length is limited thereto, bonded to an oxygenatom, including, but not limited to, methoxy, ethoxy, n-propoxy,isopropoxy, and the like. Preferably the alkoxy chain is 1 to 10 carbonatoms in length, more preferably 1 to 8 carbon atoms in length.

The term “cycloalkyl” as employed herein by itself or as part of anothergroup refers to cycloalkyl groups containing 3 to 9 carbon atoms.Typical examples are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, cyclooctyl and cyclononyl.

The term “halogen” or “halo” as employed herein by itself or as part ofanother group refers to chlorine, bromine, fluorine or iodine withchlorine being preferred.

The term “acyl” as employed herein by itself or as part of another grouprefers to the group —C(O)R^(g) where R^(g) is alkyl, alkenyl, alkynyl,aryl, aralkyl, aralkenyl, heteroaryl, heteroarylalkyl orheteroarylalkenyl. Preferred acyl groups are alkanoyl, aralkanoyl andaroyl groups (—C(O)R^(g) where R^(g) is C₁₋₈alkyl, C₆₋₁₀aryl(C₁₋₄)alkylor C₆₋₁₀aryl).

The term “thioacyl” as employed herein by itself or as part of anothergroup refers to the group —C(S)R^(g) where R^(g) is alkyl, alkenyl,alkynyl, aryl, aralkyl, aralkenyl, heteroaryl, heteroarylalkyl orheteroarylalkenyl, preferably C₁₋₈alkyl.

The term “thiocarbonyl” as employed herein by itself or as part ofanother group refers to the group —C(S)—.

The term “monoalkylamine” as employed herein by itself or as part ofanother group refers to an amino group which is substituted with onealkyl group having from 1 to 6 carbon atoms.

The term “dialkylamine” as employed herein by itself or as part ofanother group refers to an amino group which is substituted with twoalkyl groups, each having from 1 to 6 carbon atoms.

The term “aryl” as employed herein by itself or as part of another grouprefers to monocyclic- or bicyclic aromatic groups containing from 6 to14 carbons in the ring portion, preferably 6-10 carbons in the ringportion, such as phenyl, naphthyl or tetrahydronaphthyl.

The term “aralkyl” or “arylalkyl” as employed herein by itself or aspart of another group refers to C₁₋₆alkyl groups as discussed abovehaving an aryl substituent, such as benzyl, phenylethyl or2-naphthylmethyl.

The terms “heterocyclic,” “heterocyclo” or “heterocycle” as employedherein by themselves or as part of larger groups refers to a saturatedor wholly or partially unsaturated 3-7 membered monocyclic, or 7-10membered bicyclic ring system, which consists of carbon atoms and fromone to four heteroatoms independently selected from the group consistingof O, N, and S, wherein the nitrogen and sulfur heteroatoms can beoptionally oxidized, the nitrogen can be optionally quaternized, andincluding any bicyclic group in which any of the above-definedheterocyclic rings is fused to a benzene ring, and wherein theheterocyclic ring can be substituted on carbon or on a nitrogen atom ifthe resulting compound is stable. Especially useful are rings containingone oxygen or sulfur, one to three nitrogen atoms, or one oxygen orsulfur combined with one or two nitrogen atoms. Examples of suchheterocyclic groups include piperidinyl, piperazinyl, 2-oxopiperazinyl,2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, pyrrolyl,4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl,imidazolinyl, imidazolidinyl, pyridyl, pyrazinyl, pyrirnidinyl,pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl,morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, quinuclidinyl,isothiazolidinyl, indolyl, indanyl, quinolinyl, isoquinolinyl,benzimidazolyl, thiadiazoyl, benzopyranyl, benzothiazolyl, benzoxazolyl,furyl, tetrahydrofuryl, tetrahydropyranyl, thienyl, benzothienyl,thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, andoxadiazolyl. Morpholino is the same as morpholinyl.

The term “heteroatom” is used herein to mean an oxygen atom (“O”), asulfur atom (“S”) or a nitrogen atom (“N”). It will be recognized thatwhen the heteroatom is nitrogen, it may form an NR^(y)R^(z) moiety,wherein R^(y) and R^(z) are, independently from one another, hydrogen orC₁ to C₈alkyl, or together with the nitrogen to which they are bound,form a saturated or unsaturated 5-, 6-, or 7-membered ring.

The term “heteroaryl” as employed herein refers to groups having 5 to 14ring atoms; 6, 10 or 14 π electrons shared in a cyclic array; andcontaining carbon atoms and 1, 2 or 3 oxygen, nitrogen or sulfurheteroatoms (where examples of heteroaryl groups are: thienyl,benzo[b]thienyl, naphtho[2,3-b]thienyl, thianthrenyl, furyl, pyranyl,isobenzofuranyl, benzoxazolyl, chromenyl, xanthenyl, phenoxathiinyl,2H-pyrrolyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl,pyrimidinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, indolyl,indazolyl, purinyl, 4H-quinolizinyl, isoquinolyl, quinolyl,phthalazinyl, naphthyridinyl, quinazolinyl, cinnolinyl, pteridinyl,4αH-carbazolyl, carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl,perimidinyl, phenanthrolinyl, phenazinyl, isothiazolyl, phenothiazinyl,isoxazolyl, furazanyl and phenoxazinyl groups).

The expression “prodrug” denotes a derivative of a known direct actingdrug, which derivative has enhanced delivery characteristics andtherapeutic value as compared to the drug, and is transformed into theactive drug by an enzymatic or chemical process. Useful prodrugs arethose where R⁴, R⁵ and/or R⁶ are —CO₂R^(w), where R^(w) is definedabove. See, U.S. Pat. No. 5,466,811 and Saulnier et al., Bioorg. Med.Chem. Lett. 4:1985-1990 (1994).

The term “substituted”, as used herein, means that one or more hydrogensof the designated moiety are replaced with a selection from theindicated group, provided that no atom's normal valency is exceeded, andthat the substitution results in a stable compound. When a substituentis keto (i.e., ═O), then 2 hydrogens attached to an atom of the moietyare replaced.

By “stable compound” or “stable formula” is meant herein a compound thatis sufficiently robust to survive isolation to a useful degree of purityfrom a reaction mixture and formulation into an efficacious therapeuticagent.

A first preferred group of compounds falling within the scope of thepresent invention include compounds of Formula I wherein X is sulfur oroxygen; Y is a covalent bond or —NH—; R¹ is hydrogen, amino, hydroxy orhalogen; R⁴, R⁵ and R⁶ are independently hydrogen, C₁₋₄alkyl, amino,cyano, C₁₋₄alkoxy or hydroxy, and are preferably all hydrogen; one of R²or R³ is hydrogen, C₁₋₆alkyl (optionally substituted with hydroxy,amino, carboxy or aminocarbonyl), C₁₋₆alkylthio or C₁₋₆alkoxy; and theother of R² or R³ is aminoacyl, acylamino, aminosulfonyl, sulfonylamino,aminocarbonylamino, alkoxycarbonylamino, optionally substitutedoxazolyl, optionally substituted isoxazolyl, optionally substitutedbenzothienyl, optionally substituted furanyl, optionally substitutedpyrazolyl or optionally substituted pyridyl.

Specific compounds within the scope of the invention include thecompounds described in the Examples, such as the following:

4-[4-(4-chlorophenyl)thiazol-2-yl]-5-methylthiothiophene-2-carboxamidine;

4-phenyl-5-methylthiothiophene-2-carboxamidine;

4-[4-(2,4-dichlorophenyl)thiazol-2-yl]-5-methylthiothiophene-2-carboxamidine;

4-(4-methylthiazol-2-yl)-5-methylthiothiophene-2-carboxamidine;

methyl4-[4-(4-phenylphenyl)thiazol-2-yl]-5-methylthiothiophene-2-carboxylate;

4-[4-(3-methoxyphenyl)thiazol-2-yl]-5-methylthiothiophene-2-carboxamidine,

4-[4-(3-hydroxyphenyl)thiazol-2-yl]-5-methylthiothlophene-2-carboxamidine,

4-(4-phenylthiazol-2-yl)-5-methylthiothiophene-2-carboxamidine,

4-[4-(4-nitrophenyl)thiazol-2-yl]-5-methylthiothiophene-2-carboxamidine,

4-[4-(3,4-ethylenedioxyphenyl)thiazol-2-yl]-5-methylthiothiophene-2-carboxamidine,

4-[4-(3,4-propylenedioxyphenyl)thiazol-2-yl]-5-methylthiothiophene-2-carboxamidine,

4-[4-(4-(naphth-2-yl)thiazol-2-yl]-5-methylthiothiophene-2-carboxamidine,

4-isopropylsulfonyl-5-methylthiothiophene-2-carboxamidine;

4-phenyl-5-methylthiothiophene-2-carboxamidine;

4-[4-(4-chlorophenyl)thiazol-2-yl]-methylthlothiophene-2-carboxamidine;

4-[4-(4-phenylphenyl)thiazol-2-yl]-5-methylthiothiophene-2-carboxamidine;

4-[4-(4-methoxyphenyl)thiazol-2-yl]-5-methylthiothiophene-2-carboxamidine;

4-(2-naphthylthiazol-2-yl)-5-methylthiothiophene-2-carboxamidine;

4-[4-(4-chloro-3-methylphenyl)thiazol-2-yl]-5-methylthiothiophene-2-carboxamidine;

4-(5-methyl-4-phenylthiazol-2-yl)-5-methylthlothiophene-2-carboxamidine;

4-[4-(4-chloro-3-nitrophenyl)thiazol-2-yl]-5-methylthiothiophene-2-carboxamidine;

4-(5-phenyloxazol-2-yl)-5-methylthiothiophene-2-carboxamidine;

4-[4-(3-fluoro-5-trifluoromethylphenyl)-5-methylthiazol-2-yl]-5-methylthiothiophene-2-carboxamidine;

4-[4-(3,5-bis(trifluoromethyl)phenyl)-5-methyl-thiazol-2-yl]-5-methylthiothiophene-2-carboxamidine;

4-[4-(3-fluoro-5-trifluoromethylphenyl)thiazol-2-yl]-5-methylthiothiophene-2-carboxamidine;

4-[4-(3-bromophenyl)thiazol-2-yl]-5-methylthiothiophene-2-carboxamidine;

4-[4-(3,4-methylenedioxyphenyl)thiazol-2-yl]-5-methylthiothlophene-2-carboxamidine;

4-[4-(4-methylphenyl)thiazol-2-yl]-5-methylthlothiophene-2-carboxamidine;

4-[4-(3,5-bis(trifluoromethyl)phenyl)thiazol-2-yl]-5-methylthiothiophene-2-carboxamidine;

4-[4-(2-methoxyphenyl)thiazol-2-yl)-5-methylthiothiophene-2-carboxamidine;

4-(4-phenylimidazol-2-yl]-5-methylthiothiophene-2-carboxamidine;

4-(4-(2,4-dimethoxyphenyl)thiazol-2-yl-5-methyithiothiophene-2-carboxamidine;

4-(4-benzylthiazol-2-yl)-5-methylthiothiophene-2-carboxamidine;

4-[4-(3,4-dichlorophenyl)thiazol-2-yl]-5-methylthiothiophene-2-carboxamidine;

4-[4-(3-methylphenyl)thiazol-2-yl]-5-methylthiothiophene-2-carboxamidine;

4-[4-(3,5-dimethoxyphenyl)thiazol-2-yl]-5-methylthiothiophene-2-carboxamidine;

4-[4-(2-methylphenyl)thiazol-2-yl]-5-methylthiothlophene-2-carboxamidine;

4-[4-(2,5-dimethoxyphenyl)thiazol-2-yl]-5-methylthiothiophene-2-carboxamidine;

4-(4,5-diphenylthiazol-2-yl)-5-methylthiothiophene-2-carboxamidine;

4-(2-phenyl)thiazol-4-yl-5-methylthiothiophene-2-carboxamidine;

4-[4-(2-chloro-3-pyridyl)thiazol-2-yl]-5-methylthiothiophene-2-carboxamdine;

4-[4-(phenoxymethyl)thiazol-2-yl]-5-methylthiothiophene-2-carboxamidine;

4-(4-cyclohexylthiazol-2-yl)-5-methylthiothophene-2-carboxamidine;

4-[4-(4-chlorophenyl)thiazol-2-yl]-5-methylthiothiophene-2-carboxamidine;

4-[4-(2-hydroxyphenyl)thiazol-2-yl]-5-methylthiothiophene-2-carboxamidine;

4-[4-(3-trifluoromethoxyphenyl)thiazol-2-yl]-5-methylthiothiophene-2-carboxamidine;

4-[4-(2-chloro-4-pyridyl)thiazol-2-yl]-5-methylthlothiophene-2-carboxamidine;

4-(5-phenyl-2-pyridyl)-5-methylthiothiophene-2-carboxamidine;

4-[2-(2-chlorophenylamino)thiazol-4-yl]-5-methylthiothiophene-2-carboxamidine;

4-[2-(3-methoxyphenylamino)thiazol-4-yl]-5-methylthlothlophene-2-carboxamidine;

4-[2-(phenylamino)thiazol-4-yl]-5-methylthiothlophene-2-carboxamidine;

4-[2-(2,5-dimethoxyphenylamino)thiazol-4-yl]-5-methylthlothiophene-2-carboxamidine;

4-(2-aminothiazol-4-yl)-5-methylthiothiophene-2-carboxamidine;

4-[2-(4-chloro-2-methylphenylamino)thiazol-4-yl]-5-methylthiothiophene-2-carboxamidine;

4-[2-(4-dimethylaminophenylamino)thiazol-4-yl]-5-methylthiothiophene-2-carboxamidine;

4-[2-(4-methoxyphenylamino)thiazol-4-yl]-5-methylthiothiophene-2-carboxamidine;

4-[4-(4-hydroxy-3-methoxyphenyl)thiazol-2-yl]-5-methylthiothiophene-2-carboxamidine;

4-[4-(3-hydroxy-4-methoxyphenyl)thiazol-2-yl]-5-methylthlothiophene-2-carboxamidine;

4-[2-(2-fluorophenylamino)thiazol-4-yl]-5-methylthiothiophene-2-carboxamidine;

4-[2-(2,4,5-trimethylphenyl)aminothiazol-4-yl]-5-methylthiothiophene-2-carboxamidine;

4-[2-(3-chloro-2-methylphenyl)aminothiazol-4-yi]-5-methylthlothiophene-2-carboxamidine;

4-[2-(2-isopropylphenyl)aminothiazol-4-yl]-5-methylthiothiophene-2-carboxamidine;

4-[2-(4-benzyloxyphenyl)aminothiazol-4-yl]-5-methylthiothiophene-2-carboxamidine;

4-[2-(2-bromophenyl)aminothiazol-4-yl]-5-methylthiothiophene-2-carboxamidine;

4-[2-(2,5-dichlorophenyl)aminothiazol-4-yl]-5-methylthiothiophene-2-carboxamidine;

4-[2-(2-bromo-4-methylphenyl)aminothiazol-4-yl]-5-methylthiothlophene-2-carboxamidine;

4-[2-(2,3-dichlorophenyl)aminothiazol-4-yl]-5-methylthiothiophene-2-carboxamidine;

4-[2-(3 ,4,5-trimethoxyphenyl)aminothiazol-4-yl]-5-methylthiothiophene-2-carboxamidine;

4-[2-(2-piperidinylethyl)aminothiazol-4yl]-5-methylthiothiophene-2-carboxamidine;

4-[2-(4-methylphenyl)aminothiazol-4-yl]-5-methylthiothiophene-2-carboxamidine;

4-(4-phenyloxazol-2-yl)-5-methylthiothiophene-2-carboxamidine;

4-[2-(diphenylmethyl)aminothiazol-4-yl]-5-methylthiothiophene-2-carboxamidine;and

4-[2-(3-phenylpropyl)aminothiazol-4-yl]-5-methylthiothiophene-2-carboxamidine,

as well as pharmaceutically acceptable salts thereof, for example thehydrochloride, hydrobromide and acetate salts thereof, or a prodrugthereof.

A second preferred group of compounds falling within the scope of thepresent invention include compounds of Formula I wherein X is sulfur oroxygen; Y is a covalent bond or —NH—; Z is NR⁵R⁶; R¹ is hydrogen, amino,hydroxy or halogen; R⁴, R⁵ and R⁶ are independently hydrogen, C₁₋₄alkyl,amino, C₁₋₄alkoxy or hydroxy, and are preferably all hydrogen; one of R²or R³ is hydrogen, C₁₋₆alkylthio, C₁₋₆alkyl optionally substituted withOH, NH₂, COOH or aminocarbonyl, or C₁₋₆alkoxy; and the other of R² or R³is:

where:

Ar is a group selected from the group consisting of phenyl, thiazolyl,thiazolinyl, oxazolyl, isothiazolyl, isoxazolyl, furanyl, imidazolyl,pyridyl, pyrimidinyl, pyrazinyl, thienyl (thiophenyl), tetrazolyl,pyrrolyl, pyrazolyl, oxadiazolyl, oxazolinyl, isoxazolinyl,imidazolinyl, triazolyl, pyrrolinyl, benzothiazolyl, benzothienyl,benzimidazolyl, 1,3-oxazolidin-2-onyl, imidazolin-2-onyl (preferablyphenyl, thiazolyl, thiazolinyl, oxazolinyl, isothiazolyl, isoxazolyl,imidazolyl, pyridyl, pyrimidinyl, thienyl, pyrrolyl, oxazolinyl andbenzothienyl), any of which can optionally include an exocyclic ═O(keto) or ═NR^(v) (imino) group, where R^(v) is alkyl, aryl, aralkyl,alkylamino, arylimino or aralkylimino; and

R⁸ and R⁹ are independently selected from the group consisting ofhydrogen, halogen, amino, mono(C₁₋₄)alkylamino, di(C₁₋₄)alkylamino,arylamino, mono- and di-(C₆₋₁₄)arylamino, mono- anddi-(C₆₋₁₄)ar(C₁₋₆)alkylamino, formylamino, C₂₋₆acylamino, aminocarbonyl,C₂₋₈aminoacyl, C₂₋₆thioacylamino, aminothiocarbonyl, C₂₋₈ aminothioacyl,C₁₋₆alkyl, C₃₋₈cycloalkyl, C₁₋₆alkoxy, carboxy, carboxy(C₁₋₆)alkyl,C₂₋₈alkoxycarbonyl, nitro, cyano, trifluoromethyl, thiazolyl,thiazolinyl, oxazolyl, isothiazolyl, isoxazolyl, furanyl, imidazolyl,pyridyl, pyrimidinyl, pyrazinyl, thienyl (thiophenyl), tetrazolyl,pyrrolyl, pyrazolyl, oxadiazolyl, oxazolinyl, isoxazolinyl,imidazolinyl, triazolyl, pyrrolinyl, benzothiazolyl, benzothienyl,benzimidazolyl, 1,3-oxazolidin-2-onyl, imidazolin-2-onyl, C₆₋₁₄aryloxy,C₁₋₆alkylthio, C₆₋₁₄arylthio, C₆₋₁₄aryl, or C₆₋₁₄ar(C₁₋₆)alkyl, whereinthe aforementioned heteroaryl groups and the aryl portions ofC₆₋₁₄aryloxy, mono- and di C₆₋₁₄aryl amino, mono- and di-C₆₋₁₄ar(C₁₋₆)alkylamino, C₆₋₁₄arylthio, C₆₋₁₄ar(C₁₋₆)alkyl, andC₆₋₁₄aryl can be further optionally substituted, preferably by one, twoor three of halogen, hydroxy, amino, mono(C₁₋₄)alkylamino,di(C₁₋₄)alkylamino, formylamino, C₁₋₄acylamino, C₁₋₄aminoacyl, mono- ordi-(C₁₋₄)alkylaminocarbonyl, thiocarbonylamino, C₁₋₄thioacylamino,aminothiocarbonyl, C₁₋₄alkoxy, C₆₋₁₀aryloxy, aminocarbonyloxy, mono- ordi(C₁₋₄)alkylaminocarbonyloxy, mono- or di(C₆₋₁₀)arylaminocarbonyloxy,mono- or di(C₇₋₁₅)aralkylaminocarbonyloxy, C₁₋₄alkylsulfonyl,C₆₋₁₀arylsulfonyl, (C₇₋₁₅)aralkylsulfonyl, C₁₋₄alkylsulfonylamino,C₆₋₁₀arylsulfonylamino, (C₇₋₁₅)aralkylsulfonylamino, aminosulfonyl,mono- and di-alkylaminosulfonyl, mono- and di-arylaminosulfonyl, mono-and di-aralkylamninosulfonyl, C₁₋₄alkoxycarbonylamino,C₇₋₁₅aralkoxycarbonylamino, C₆₋₁₀aryloxycarbonylamino, mono- ordi-(C₁₋₄)alkylaminothiocarbonyl, C₇₋₁₅aralkoxy, carboxy,carboxy(C₁₋₄)alkyl, C₁₋₄alkoxycarbonyl, C₁₋₄alkoxycarbonylalkyl,carboxy(C₁₋₄)alkoxy, alkoxycarbonylalkoxy, nitro, cyano,trifluoromethyl, C₁₋₄alkylthio and C₆₋₁₀arylthio, or by3,4-methylenedioxy, 3,4-ethylenedioxy, and 3,4-propylenedioxy.

Preferred values of R⁸ and R⁹ are halogen, C₁₋₆alkyl, C₁₋₄alkoxy,hydroxy, nitro, trifluoromethyl, C₆₋₁₀aryl (further optionallysubstituted by one or two of chloro, halogen, C₁₋₆alkyl, C₁₋₆alkoxy,hydroxy, nitro, trifluoromethyl, carboxy, 3,4-methylenedioxy,3,4-ethylenedioxy, 3,4-propylenedioxy, or amino), 4-phenylphenyl(biphenyl), C₁₋₆aminoalkyl, carboxy, C₁₋₆alkyl, 3,4-methylenedioxy,3,4-ethylenedioxy, 3,4-propylenedioxy, amino, C₁₋₆alkanoylamino,C₆₋₁₄aroylamino, C₁₋₆hydroxyalkyl, thienyl (further optionallysubstituted by one or two of chloro, amino, methyl, methoxy, or hydroxy)and tetrazolyl. More preferably, R² is thienyl, oxazolyl, or thiazolyl,optionally substituted by any of the aforementioned groups.

Examples of preferred R⁸ and R⁹ groups include 4-chlorophenyl,2,4-dichlorophenyl, methyl, 4-nitrophenyl, 3-nitrophenyl,4-methoxyphenyl, 3-methoxyphenyl, 2-methoxyphenyl,3-(2,4-dimethylthien-5-yl)phenyl, 3-hydroxyphenyl,5-(carboxymethyl)thien-2-yl, phenyl, 3,4-ethylenedioxyphenyl,3,4-propylenedioxyphenyl, naphth-2-yl, 3-phenyl-4-(tetrazol-5-yl)phenyl,2,4-dichlorophenyl), 4-phenylphenyl, 3-methoxyphenyl, 3-hydroxyphenyl,3-phenylphenyl, phenyithiomethyl, 2-chloro-4,5-dimethoxyphenyl,4-chloro-3-methylphenyl, 5-methyl-4-phenyl, 4-chloro-3-nitrophenyl,3-fluoro-5-trifluoromethylphenyl, 3,5-bis(trifluoromethyl),3-fluoro-5-trifluoromethylphenyl, 3-bromophenol,3,4-methylenedioxyphenyl, 4-methylphenyl, 3-methylphenyl,3,5-bis(trifluoromethyl)phenyl, 2-methoxyphenyl, 6-phenyl-2-pyridyl,2,4-dimethoxyphenyl, 3,4-dimethoxyphenyl, benzyl, 3,4-dichlorophenyl,3-methylphenyl, 3,5-dimethoxyphenyl, 2-methylphenyl,2,5-dimethoxyphenyl, 2-chloro-3-pyridyl, phenoxymethyl, cyclohexyl,2-hydroxyphenyl, 3-trifluoromethoxyphenyl, 2-chloro-4-pyridyl,3-chloro-4-pyridyl, 2-chlorophenylamino, 3-methoxyphenylamino,phenylamino, 2,5-dimethoxyphenylamino, amino,4-chloro-2-methylphenylamino, 4-dimethylaminophenylamino,4-methoxyphenylamino, 4-hydroxy-3-methoxyphenyl,3-hydroxy-4-methoxyphenyl, 2-fluorophenylamino,2,4,5-trimethylphenylamino, 3-chloro-2-methylphenylamino,2-isopropylphenylamino, 4-benzyloxyphenylamino, 2-bromophenylamino,2,5-dichlorophenylamino, 2-bromo-4-methylphenylamino,2,3-dichlorophenylamino, 3,4,5-trimethoxyphenylamino,2-piperidinylethylamino, 4-methylphenylamino, 2-thienyl,2-5,6,7,8-tetrahydronaphthyl, 3-(2-phenoxyacetic acid)phenyl,2-(2-phenoxyacetic acid)phenyl, diphenylmethylamino,3-phenylpropylamino, 3-phenylphenyl, phenylthiomethyl,2-chloro-4,5-dimethoxyphenyl, and isopropyl.

A third preferred group of compounds are those of Formula I wherein:

X is sulfur;

Y is a covalent bond;

Z is NR⁵R⁶;

R¹ is hydrogen;

R³ is methylthio or methyl;

R⁴, R⁵ and R⁶ are all hydrogen; and

R² is Formula II, where Ar is phenyl, thiazolyl, oxazolyl, benzothienyl,pyridyl, or imidazolyl; and R⁸ and R⁹ are independently hydrogen, orC₆₋₁₀aryl or heterocycle, optionally substituted by one, two or three ofchloro, hydroxy, C₁₋₄alkyl, C₃₋₆cycloalkyl, C₁₋₄alkoxy, amino, carboxy,phenyl, naphthyl, biphenyl, hydroxyphenyl, methoxyphenyl,dimethoxyphenyl, carboxyalkoxyphenyl, alkoxycarbonylalkoxy,carboxyethoxy, alkylsulfonylaminophenyl, arylsulfonylaminophenyl,acylsulfonylaminophenyl, aralkylsulfonylaminophenyl,heteroarylsulfonylaminophenyl where the heteroaryl portion is optionallyhalo or C₁₋₆alkyl substituted, chlorophenyl, dichlorophenyl,aminophenyl, carboxyphenyl, nitrophenyl, or by 3,4-methylenedioxy,3,4-ethylenedioxy, and 3,4-propylenedioxy.

A fourth preferred group of compounds are those of Formula I wherein:

X is sulfur;

Y is a direct covalent bond;

Z is NR⁵R⁶;

R¹ is hydrogen;

R² is alkyl, ar(alkyl), alkylsulfonyl, —SO₂-alkyl, amido, amidino, or

where

Ar is an aromatic or heteroaromatic group selected from the groupconsisting of phenyl, thiazolyl, oxazolyl, imidazolyl and pyridyl;

R⁸ and R⁹ are independently selected from the group consisting ofhydrogen, carboxy, phenyl, naphthyl, alkyl, pyridyl, oxazolyl, furanyl,cycloalkyl and amino, any of which may be optionally substituted with 1to 3 substituents independently selected from the group consisting ofhalogen, alkyl, haloalkyl, alkaryl, heteroaryl, phenyl, naphthyl,alkoxy, aryloxy, hydroxy, amino nitro, thiophenyl, benzothiophenyl,fluorenyl, 3,4-ethylenedioxy, 3,4-methylenedioxy, 3,4-propylenedioxy,arylsulfonamido, alkylsulfonamido and aryloxy, each of said 1 to 3substituents may be further optionally substituted with one or moregroups selected from alkoxy, haloalkyl, halogen, alkyl, amino, acetyl,hydroxy, dialkylamino, dialkylamino acyl, monoalkylaminoacyl,—SO₂-heteroaryl, —SO₂-aryl, or aryl;

R³ is —SO₂-alkyl, trifluoromethyl, S(O)-alkyl, hydrogen, alkoxy,alkylthio, alkyl, aralkylthio; and

R⁴, R⁵, R⁶ are hydrogen.

Preferred compounds of this embodiment are those where Ar is athiazolyl, preferably thiazol-2-yl or thiazol-4-yl, and at least one ofR⁸ and R⁹ is substituted phenyl, most preferably on the 4-position ofthe thiazol-2-yl group. Also preferred are compounds where R² is a4-phenylthiazol-2-yl group wherein said phenyl is further optionallysubstituted, and R³ is methylthio.

A fifth preferred group of compounds are those of Formula III:

or a pharmaceutically acceptable salt or prodrug thereof, where

A is methylthio or methyl;

G′ is —O—, —S—, —NH—, or a covalent bond;

n is an integer from 1-10, preferably from 1-6;

m is an integer from 0-1; and

R′ and R″ are independently selected from hydrogen, alkyl, aryl oraralkyl, or R′ and R″ are taken together with the N atom to which theyare attached form a 3-8 membered heterocyclic ring, optionallycontaining an additional O, N, or S atom, and when said 3-8 memberedheterocyclic ring contains an additional N atom, said additional N atomis optionally substituted by hydrogen, C₁₋₄alkyl, C₆₋₁₀aryl,C₆₋₁₀ar(C₁₋₄)alkyl, acyl, alkoxycarbonyl or benzyloxycarbonyl.

Most preferred compounds of Formula III are those for which R′ and R″,taken together with the N atom to which they are attached, form a ringselected from piperazinyl, pyrrolidinyl, piperidinyl or morpholinyl,which are further optionally substituted with 1 to 4 non-hydrogensubstituents selected from halogen, hydroxy, amino, monoalkylamino,dialkylamino, formylamino, acylamino, aminoacyl, mono- ordi-alkylaminocarbonyl, thiocarbonylamino, thioacylamino,aminothiocarbonyl, alkoxy, aryloxy, aminocarbonyloxy, mono- ordi-alkylaminocarbonyloxy, mono- or diarylaminocarbonyloxy, mono- ordiarakylaminocarbonyloxy, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl,alkylsulfonylamino, arylsulfonylamino, arakylsulfonylamino,alkoxycarbonylamino, aralkoxycarbonylamino, aryloxycarbonylamino, mono-or di-alkylaminothiocarbonyl, aralkoxy, carboxy, carboxyalkyl,alkoxycarbonyl, alkoxycarbonylalkyl, nitro, cyano, trifluoromethyl,alkylthio and arylthio, where each of these substituents has thepreferred values set forth for Formulae I and II above.

Examples of preferred compounds of Formula III include:

5-methylthio-4-[4-(3-{[N-(2-morpholin-4-ylethyl)carbamoyl]methoxy}phenyl)(1,3-thiazol-2-yl)]thiophene-2-carboxamidine,

5-methylthio-4-{4-[3-(2-morpholin-4-yl-2-oxoethoxy)phenyl](1,3-thiazol-2-yl)}thiophene-2-carboxamidine,

5-methylthio-4-{4-[3-(2-oxo-2-piperazinylethoxy)phenyl](1,3-thiazol-2-yl)}thiophene-2-carboxamidine,

4-[4-(3-{[N-(2-aminoethyl)carbamoyl]methoxy}phenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxamidine,

4-(4-{3-[2-(4-acetylpiperazinyl)-2-oxoethoxy]phenyl}(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxamidine,

4-(4-{3-[2-(4-methylpiperazinyl)-2-oxoethoxy]phenyl}(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxamidine,the compound described in Example 151,

5-methylthio-4-[4-(3-{2-oxo-2-[4-benzylpiperazinyl]ethoxyphenyl)(1,3-thiazol-2-yl)]thiophene-2-carboxamidine,

(D,L)-4-(4-{3-[2-(3-aminopyrrolidinyl)-2-oxoethoxy]phenyl}(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxamidine,

5-methylthio-4-(4-[3-(2-oxo-2-piperidylethoxy)phenyl](1,3-thiazol-2-yl)}thiophene-2-carboxamidine,

(D,L)-ethyl1-(2-{3-[2-(5-amidino-2-methylthio-3-thienyl)-1,3-thiazol-4-yl]phenoxy}acetyl)piperidine-2-carboxylate,

5-methylthio-4-{4-[3-(2-oxo-2-pyrrolidinylethoxy)phenyl](1,3-thiazol-2-yl)}thiophene-2-carboxamidine,5-methylthio-4-[4-(3-{2-oxo-2-[4-benzylpiperidyl]ethoxy}phenyl)(1,3-thiazol-2-yl)]thiophene-2-carboxamidine,

(D,L)-4-(4-{3-[2-(3-methylpiperidyl)-2-oxoethoxy]phenyl}(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxamidine,

4-(4-{3-[2-(4-methylpiperidyl)-2-oxoethoxy]phenyl}(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxamidine,

4-(4-{3-[2-(2-azabicyclo[4.4.0]dec-2-yl)-2-oxoethoxy]phenyl}(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxamidine,

(D,L)-ethyl1-(2-{3-[2-(5-amidino-2-methylthio-3-thienyl)-1,3-thiazol-4-yl]phenoxy}acetyl)piperidine-3-carboxylate,

5-methylthio-4-{4-[3-(2-oxo-2-(1,2,3,4-tetrahydroquinolyl)ethoxy)phenyl](1,3-thiazol-2-yl)}thiophene-2-carboxamidine,

ethyl1-(2-{3-[2-(5-amidino-2-methylthio-3-thienyl)-1,3-thiazol-4-yl]phenoxy}acetyl)piperidine-4-carboxylate,

4-(4-{3-[2-((3R)-3-hydroxypiperidyl)-2-oxoethoxy]phenyl}(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxamidine,

D,L-4-(4-{3-[2-(2-ethylpiperidyl)-2-oxoethoxy]phenyl}(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxamidine,

4-(4-{3-[2-((3S)-3-hydroxypyrrolidinyl)-2-oxoethoxy]phenyl}(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxamidine,

D,L4-[4-(3-{2-[3-(hydroxymethyl)piperidyl]-2-oxoethoxylphenyl}(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxamidine,

4-{4-[3-(2-{(2R)-2-[(phenylamino)methyl]pyrrolidinyl}-2-oxoethoxy)phenyl](1,3-thiazol-2-yl)}-5-methylthiothiophene-2-carboxamidine,

4-[4-(3-{2-[(3R)-3-(methoxymethyl)pyrrolidinyl]-2-oxoethoxy}phenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxamidine,

1-(2-{3-[2-(5-amidino-2-methylthio-3-thienyl)-1,3-thiazol-4-yl]phenoxy}acetyl)piperidine-3-carboxamide,and

2-{3-[2-(5-{[(tert-butoxy)carbonylamino]iminomethyl}-2-methyl-3-thienyl)-1,3-thiazol-4-yl]phenoxylaceticacid;

or pharmaceutically acceptable salts or prodrugs thereof.

A sixth preferred group of compounds are those of Formula IV:

or a pharmaceutically acceptable salt or prodrug thereof, where

A is methylthio or methyl; and

R′″ is hydrogen, C₆₋₁₄aryl, C₁₋₆alkyl, C₁₋₆alkoxy (C₆₋₁₄)aryl,amino(C₆₋₁₄)aryl, monoalkylamino(C₆₋₁₄)aryl, dialkylamino(C₆₋₁₄)aryl,C₆₋₁₀ar(C₁₋₆)alkyl, heterocycle(C₂₋₆)alkyl such as morpholinoalkyl,piperazinylalkyl and the like, C₁₋₆alk(C₆₋₁₄)aryl, amino(C₁₋₆)alkyl,mono(C₁₋₆)alkylamino(C₁₋₆)alkyl, di(C₁₋₆)alkylamino(C₁₋₆)alkyl,hydroxy(C₆₋₁₄)aryl, or hydroxy(C₁₋₆)alkyl, where the aryl andheterocyclic rings can be further optionally substituted by 1-4non-hydrogen substituents selected from halogen, hydroxy, amino,mono(C₁₋₆)alkylamino, di(C₁₋₆)alkylamino, formylamino, (C₁₋₆)acylamino,amino(C₁₋₆)acyl, mono- or di-(C₁₋₆)alkylaminocarbonyl,thiocarbonylamino, (C₁₋₆)thioacylamino, aminothiocarbonyl, (C₁₋₆)alkoxy,(C₆₋₁₀)aryloxy, aminocarbonyloxy, mono- ordi-(C₁₋₆)alkylaminocarbonyloxy, mono- or di-(C₆₋₁₀)arylaminocarbonyloxy,mono- or di(C₆₋₁₀)ar(C₁₋₆)alkylaminocarbonyloxy, (C₁₋₆)alkylsulfonyl,(C₆₋₁₀)arylsulfonyl, (C₆₋₁₀)ar(C₁₋₆)alkylsulfonyl,(C₁₋₆)alkylsulfonylamino, C₆₋₁₀arylsulfonylamino,(C₆₋₁₀)ar(C₁₋₆)alkylsulfonylamino,(C₁₋₆)alkoxycarbonylamino,(C₆₋₁₀)ar(C₁₋₆)alkoxycarbonylamino, C₆₋₁₀aryloxycarbonylamino, mono- ordi-(C₁₋₆)alkylaminothiocarbonyl, (C₆₋₁₀)ar(C₁₋₆)alkoxy, carboxy,(C₁₋₆)carboxyalkyl, C₁₋₆alkoxycarbonyl, (C₁₋₆)alkoxycarbonyl(C₁₋₆)alkyl,nitro, cyano, trifluoromethyl, (C₁₋₆)alkylthio and C₆₋₁₀arylthio.

Examples of preferred compounds of Formula IV include:

4-{2-[(3-methoxyphenyl)amino](1,3-thiazol-4-yl)}-5-methylthiothiophene-2-carboxamidine,

4-{2-[(4-methoxyphenyl)amino](1,3-thiazol-4-yl)}-5-methylthiothiophene-2-carboxamidine,

4-(2-{[4-(dimethylamino)phenyl]amino}(1,3-thiazol-4-yl)}-5-methylthiothiophene-2-carboxamidine,

4-{2-[(4-chloro-2-methylphenyl)amino](1,3-thiazol-4-yl)}-5-methylthiothiophene-2-carboxamidine,

4-{2-[(diphenylmethyl)amino](1,3-thiazol-4-yl)}-5-methylthiothiophene-2-carboxamidine,

5-methylthio-4-{2-[(3-phenylpropyl)amino](1,3-thiazol-4-yl)}thiophene-2-carboxamidine,

5-methylthio-4-{2-[(2,4,5-trimethylphenyl)amino](1,3-thiazol-4-yl)}thiophene-2-carboxamidine,

4-{2-[(2-fluorophenyl)amino](1,3-thiazol-4-yl}-5-methylthiothiophene-2-carboxamidine,

4-{2-[(3-chloro-2-methylphenyl)amino](1,3-thiazol-4-yl)}-5-methylthiothiophene-2-carboxamidine,

4-(2-{[2-(methylethyl)phenyl]amino}(1,3-thiazol-4-yl))-5-methylthiothiophene-2-carboxamidine,

5-methylthio-4-(2-{[4-(phenylmethoxy)phenyl]amino}(1,3-thiazol-4-yl))thiophene-2-carboxamidine,

4-(2-[(2-bromophenyl)amino](1,3-thiazol-4-yl)}-5-methylthiothiophene-2-carboxamidine,

4-{2-[(2,6-dichlorophenyl)amino](1,3-thiazol-4-yl)}-5-methylthiothiophene-2-carboxamidine,

4-{2-[(2-bromomethylphenyl)amino](1,3-thiazol-4-yl)}-5-methylthiothiophene-2-carboxamidine,

5-methylthio-4-{2-[(2-morpholin-4-ylethyl)amino](1,3-thiazol-4-yl)}thiophene-2-carboxamidine,

4-{2-[(2,3-dichlorophenyl)amino](1,3-thiazol-4-yl)}-5-methylthiothiophene-2-carboxamidine,

5-methylthio-4-{2-[(3,4,5-trimethoxyphenyl)amino](1,3-thiazol-4-yl)}thiophene-2-carboxamidine,

5-methylthio-4-{2-[(2-piperidylethyl)amino](1,3-thiazol-4-yl)}thiophene-2-carboxamidine,

4-(2-{[(4-methylphenyl)methyl]amino}(1,3-thiazol-4-yl))-5-methylthiothiophene-2-carboxamidine,

4-(2-{[4-(4-chlorophenoxy)phenyl]amino}(1,3-thiazol-4-yl))-5-methylthiothiophene-2-carboxamidine,

4-(2-{[4-phenoxyphenyl]amino}(1,3-thiazol-4-yl))-5-methylthiothiophene-2-carboxamidine,

5-methylthio-4-(2-{[4-(phenylamino)phenyl]amino}(1,3-thiazol-4-yl))thiophene-2-carboxamidine,

5-methylthio-4-(2-{[4-benzylphenyl]amino}(1,3-thiazol-4-yl))thiophene-2-carboxamidine,

5-methylthio-4-(2-{[4-(piperidylsulfonyl)phenyl]amino}(1,3-thiazol-4-yl))thiophene-2-carboxamidine,

5-methylthio-4-[2-(3-quinolylamino)(1,3-thiazol-4-yl)]thiophene-2-carboxamidine,

5-methylthio-4-[2-(2-naphthylamino)(1,3-thiazol-4-yl)]thiophene-2-carboxamidine,

4-[2-(2H-benzo[3,4-d]1,3-dioxolan-5-ylamino)(1,3-thiazol-4-yl)]-5-methylthiothiophene-2-carboxamidine,

4-(2-[(7-bromofluoren-2-yl)amino](1,3-thiazol-4-yl)}-5-methylthiothiophene-2-carboxamidine,

4-{2-[(4-cyclohexylphenyl)amino](1,3-thiazol-4-yl)}-5-methylthiothiophene-2-carboxamidine,

5-methylthio-4-(2-{[4-(phenyldiazenyl)phenyl]amino}(1,3-thiazol-4-yl))thiophene-2-carboxamidine,

5-methylthio4-(2-{[3-(hydroxymethyl)phenyl]amino}(1,3-thiazol-4-yl))-thiophene-2-carboxamidine,

4-[2-({3-[(3-methylpiperidyl)methyl]phenyl}amino)(1,3-thiazol-4-yl)]-5-methylthiothiophene-2-carboxamidine,

4-{2-[(3-hydroxyphenyl)amino](1,3-thiazol-4-yl)}-5-methylthiothiophene-2-carboxamidine,

4-(2-{[4-(carbamoylmethoxy)phenyl]amino}(1,3-thiazol-4-yl))-5-methylthiothiophene-2-carboxamidine,

5-methyl-4-{2-[(3,4,5-trimethoxyphenyl)amino](1,3-thiazol-4-yl)}thiophene-2-carboxamidine,

5-methyl-4-{2-[(4-phenoxyphenyl)amino](1,3-thiazol-4-yl)}thiophene-2-carboxamidine,

5-methyl4-[2-(phenylamino)(1,3-thiazol-4-yl)]thiophene-2-carboxamnidine,and

4-(4-isoxazol-5-yl(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxamidine;

as well as pharmaceutically acceptable salts and prodrugs thereof.

A seventh preferred group of compounds are compounds of Formula I,

or a pharmaceutically acceptable salt or prodrug thereof, wherein:

X is sulfur or oxygen, preferably sulfur;

Y is a covalent bond or —NH—, preferably a covalent bond;

Z is NR⁵R⁶;

R¹ is hydrogen, amino, hydroxy or halogen, preferably hydrogen;

R⁴, R⁵ and R⁶ are independently hydrogen, C₁₋₄alkyl, amino, C₁₋₄alkoxyor hydroxy, and are preferably all hydrogen;

R³ is hydrogen, C₁₋₆alkylthio, C₁₋₆alkyl optionally substituted with OH,NH_(2.) COOH or aminocarbonyl, or C₁₋₆alkoxy, preferably methylthio ormethyl; and

R² is

alkylsulfonylamino, aralkylsulfonylamino, aralkenylsulfonylamino,arylsulfonylamino, heteroarylsulfonylamino, di(aralkylsulfonyl)amino,di(aralkenylsulfonyl)amino, di(arylsulfonyl)amino, ordi-(heteroarylsulfonyl)amino, wherein any of the aryl or heteroarylcontaining groups can be optionally substituted on the aromatic ring; or

amino, monoalkylamino, dialkylamino, monoarylamino, diarylamino,monoalkylmonoarylamino, monoaralkylamino, diaralkylamino,monoalkylmonoaralkylamino, monoheterocycleamino, diheterocycleamino,monoalkylmonoheterocycleamino, wherein any of the aryl or heteroarylcontaining groups can be optionally substituted on the aromatic ring andwherein any of the heterocycle containing groups can be optionally ringsubstituted; or

alkanoylamino, alkenoylamino, alkynoylamino, aroylamino,aralkanoylamino, aralkenoylamino, heteroaroylamino,heteroarylalkanoylamino, any of which is optionally substituted on thearomatic ring; or

alkoxy and alkylthio, either of which is optionally substituted, oraryloxy, aralkoxy, arylthio, aralkylthio, arylsulfonyl, aralkylsulfonyl,aralkenylsulfonyl, any of which is optionally substituted on thearomatic ring; or

alkoxycarbonylamino, aralkoxycarbonylamino, aryloxycarbonylamino,wherein any of the aryl containing groups can be optionally substitutedon the aromatic ring; or

formylamino, H(S)CNH—, or thioacylamino.

Preferred optional substituents are halogen, C₁₋₆alkyl, C₁₋₆alkoxy,hydroxy, nitro, trifluoromethyl, C₆₋₁₀aryl, C₆₋₁₀aryloxy,C₆₋₁₀arylmethoxy (wherein the aryl groups on these aryl-containingsubstituents are further optionally substituted by one or two of chloro,halogen, C₁₋₆alkyl, C₁₆alkoxy, phenyl, hydroxy, nitro, trifluoromethyl,carboxy, 3,4-methylenedioxy, 3,4-ethylenedioxy, 3,4-propylenedioxy, oramino), C₁₋₆aminoalkyl, carboxy, alkyl, 3,4-methylenedioxy,3,4-ethylenedioxy, 3,4-propylenedioxy, amino, mono- ordi-(C₁₋₆)alkylamino, mono- or di- C₆₋₁₀arylamino,C₁₋₆alkylsulfonylamino, C₆₋₁₀arylsulfonylamino, C₁₋₈acylamino,C₁₋₈akoxycarbonyl, C₁₋₆alkanoylamino, C₆₋₁₄aroylamino, C₁₋₆hydroxyalkyl,methylsulfonyl, phenylsulfonyl, thienyl (further optionally substitutedby one or two of chloro, amino, methyl, methoxy, or hydroxy) andtetrazolyl.

In one aspect of this embodiment, R² is preferablyC₁₋₆alkylsulfonylamino, C₆₋₁₀ar(C₁₋₆)alkylsulfonylamino,C₆₋₁₀ar(C₂₋₆)alkenylsulfonylamino, C₆₋₁₀arylsulfonylamino,heteroarylsulfonylamino, di(C₆₋₁₀ar(C₁₋₁₆)alkylsulfonyl)amino,di(C₆₋₁₀ar(C₂₋₆)alkenylsulfonyl)amino, di(C₆₋₁₀arylsulfonyl)amino, ordi-(heteroarylsulfonyl)amino, wherein any of the aryl or heteroarylcontaining groups can be optionally substituted on the aromatic ring.

Especially preferred R² groups in this embodiment of the inventioninclude C₆₋₁₀arylsulfonylamino, di-(C₆₋₁₀arylsulfonyl)amino,C₆₋₁₀ar(C₁₋₃)alkylsulfonylamino, di-(C₆₋₁₀ar(C₁₋₃)alkylsulfonyl)amino,thienylsulfonylamino, any of which is optionally substituted on thearomatic ring.

Useful values of R², when R² is a substituted sulfonylamino groupinclude biphenylsul fonylamino, bis(biphenylsulfonyl)amino,naphth-2-ylsulfonylamino, di(naphth-2-ylsulfonyl)amino,6-bromonaphth-2-ylsulfonylamino, di(6-bromonaphth-2-ylsulfonyl)amino,naphth-1-ylsulfonylamino, di(naphth-1-ylsulfonyl)amino,2-methylphenylsulfonylamino, di-(2-methylphenylsulfonyl)amino,3-methylphenylsulfonylamino, di-(3-methylphenylsulfonyl)amino,4-methylphenylsulfonylamnino, di-(4-methylphenylsulfonyl)amino,benzylsulfonylamino, 4-methoxyphenylsulfonylamino,di-(4-methoxyphenylsulfonyl)amino, 4-iodophenylsulfonylamino,di-(4-iodophenylsulfonyl)amino, 3,4-dimethoxyphenylsulfonylamino,bis-(3,4-dimethoxyphenylsulfonyl)amino, 2-chlorophenylsulfonylamino,di-(2-chlorophenylsulfonyl)amino, 3-chlorophenylsulfonylamino,di-(3-chlorophenylsulfonyl)amino, 4-chlorophenylsulfonylamino,di-(4-chlorophenylsulfonyl)amino, phenylsulfonylamino,di-(phenylsulfonyl)amino, 4-tert-butylphenylsulfonylamino,di-(4-tert-butylphenylsulfonyl)amino, 2-phenylethenylsulfonylamino, and4-(phenylsulfonyl)thien-2-ylsulfonylamino.

In another aspect of this embodiment, R² is preferably amino,mono(C₁₆)alkylamino, di(C₁₋₆)alkylamino, mono(C₆₋₁₀)arylamino,di(C₆₋₁₀)arylamino, mono(C₁₋₆)alkylmono(C₆₋₁₀)arylamino,monoar(C₁₋₆)alkylamino, di(C₆₋₁₀)ar(C₁₋₆)alkylamino,mono(C₁₋₆)alkylmono(C₆₋₁₀)ar(C₁₋₆)alkylamino, monoheteroarylamino,diheteroarylamino, mono(C₁₋₆)alkylmonoheteroarylamino, wherein any ofthe aryl or heteroaryl containing groups can be optionally substitutedon the aromatic ring.

Especially preferred R² groups in this embodiment of the inventioninclude mono(C₆₋₁₀)arylamino, mono(C₁₋₆)alkylmono(C₆₋₁₀)arylamino,mono(C₆₋₁₀)ar(C₁₋₃)alkylamino,mono(C₁₋₆)alkylmono(C₆₋₁₀)ar(C₁₋₃)alkylamino, monoheteroarylamino, andmono(C₁₋₆)alkylmonoheteroarylamino Examples of suitable heteroarylaminogroups include 1,3-thiazol-2-ylamino, imidazol-4-ylamino,quinolin-2-ylamino and quinolin-6-ylamino.

Useful values of R², when R² is a substituted amino group includeanilino, naphth-2-ylamino, naphth-1-ylamino,4-(biphenyl)thiazol-2-ylamino, 4-(phenyl)thiazol-2-ylamino,4-phenyl-5-methylthiazol-2-ylamino,4-hydroxy-4-trifluoromethylthiazol-2-ylamino, 3-phenylphenylamino,pyrimidin-2-ylamino, 4-isopropylphenylamino, 3-isopropylphenylamino,4-phenylphenylamino, 3-fluoro-4-phenylphenylamino,3,4-methylenedioxyphenylamino, n-butylphenylamino,N-methyl-N-(2-methylphenyl)amino, 3-nitrophenylamino,4-methoxyphenylamino, 3-methoxyphenylamino, 2-methoxyphenylaminno,2-methylphenylamino, 3-methylphenyl amino, 3,4-dimethylphenylamino,3-chlorophenylamino, 4-chlorophenylamino,4-(3-fluoro-4-methylphenyl)amino, 4-(indan-5-yl)amino, benzylamino,indanylmethylamino, 2,3-dihydrobenzofuranylmethyl,2-phenylimidazol-5-yl, 3-hydroxybenzyl, 3-phenoxyphenylamino,4-phenoxyphenylamino, 3-benzyloxyphenylamino, 4-benzyloxyphenylamino,quinolin-6-ylamino, quinolin-3-ylamino, 4-(phenylamino)phenylamino,4-(4-ethylphenyl)phenylamino, 4-(dimethylamino)phenylamino,4-cyclohexylphenylamino, 4-(9-ethylcarbazol-3-yl)amino,4-(t-butyl)phenylamino, and 4-methylthiophenyl amino.

In another aspect of this embodiment, R² is preferably an acylaminogroup, such as alkanoylamino, alkenoylamino, aroylamino,aralkanoylamino, aralkenoylamino, heteroaroylamino,heteroarylalkanoylamino, any of which is optionally substituted on thearomatic ring.

Especially preferred R² groups in this embodiment of the inventioninclude (C₆₋₁₀)arylcarbonylamino, C₆₋₁₀ar(C₁₋₃)alkylcarbonylamino,C₆₋₁₀ar(C₂₋₃)alkenylcarbonylamino, C₆₋₁₀aryloxy(C₁₋₃)alkylcarbonylamino,C₃₋₈cycloalkylcarbonylamino, C₁₋₄alkylcarbonylamino, andheteroarylcarbonylamino, such as furanylcarbonylamino, andquinolinylcarbonylamino.

Useful values of R², when R² is an acylamino group include3-hydroxyphenylcarbonylamino, 2-phenylethenylcarbonylamino,phenylcarbonylamino, cyclohexylcarbonylamino,4-methyl-3-nitrophenylcarbonylamino, furan-2-ylcarbonylamino,tert-butylcarbonylamino, 5-(3,5-dichlorophenoxy)furan-2-ylcarbonylamino,naphth-1-ylcarbonylamino, quinolin-2-ylcarbonylamino,4-ethoxyphenylcarbonylamino, phenoxymethylcarbonylamino, and3-methylphenylcarbonylamino.

In another aspect of this embodiment, R² is preferably C₆₋₁₀aryloxy,C₆₋₁₀ar(C₁₋₆)alkoxy, C₆₋₁₀arylsulfonyl, C₆₋₁₀ar(C )alkylsulfonyl, orC₆₋₁₀ar(C₂₋₆)alkenylsulfonyl, any of which is optionally substituted onthe aromatic ring. Especially preferred R² groups in this embodiment ofthe invention include C₆₋₁₀aryloxy, and C₆₋₁₀arylsulfonyl.

Useful values of R², when R² is an aryloxy or arylsulfonyl group includephenoxy, naphthyloxy, phenylsulfonyl, and naphthylsulfonyl.

Representative compounds within the scope of this seventh embodiment ofthe invention include:

5-methylthio-4-(6-quinolylamino)thiophene-2-carboxamidine

5-methylthio-4-[(3-phenylphenyl)amino]thiophene-2-carboxamidine

5-methylthio-4-(3-quinolylamino)thiophene-2-carboxamidine5-methylthio-4-(pyrimidin-2-ylamino)thiophene-2-carboxamidine

4-[(4-cyclohexylphenyl)amino]-5-methylthiothiophene-2-carboxamidine

methyl 4-amino-5-methylthiothiophene-2-carboxylatemethyl4-[(aminothioxomethyl)amino]-5-methylthiothiophene-2-carboxylate

5-methylthio-4-[(4-phenyl(1,3-thiazol-2-yl))amino]thiophene-2-carboxamidine

5-methylthio-4-{[4-(4-phenylphenyl)(1,3-thiazol-2-yl)]amino}thiophene-2-carboxamidine

4-[(5-methyl-4-phenyl(1,3-thiazol-2-yl))amino]-5-methylthiothiophene-2-carboxamidine

4-{[4-hydroxy-4-(trifluoromethyl)(1,3-thiazolin-2-yl)]amino}-5-methylthiothiophene-2-carboxamidine

5-methylthio-4-(2-naphthylamino)thiophene-2-carboxamidine

4-[(4-chlorophenyl)amino]-5-methylthiothiophene-2-carboxamidine

4-[(3-methylphenyl)amino]-5-methylthiothiophene-2-carboxamidine

4-[(3-methoxyphenyl)amino]-5-methylthlothiophene-2-carboxamidine

4-{[3-(methylethyl)phenyl]amino}-5-methylthiothiophene-2-carboxamidine

5-methylthio-4-[(3-nitrophenyl)amino]thiophene-2-carboxamidine

4-{[4-(methylethyl)phenyl]amino)-5-methylthiothiophene-2-carboxamidine

4-[(3,4-dimethylphenyl)amino]-5-methylthiothiophene-2-carboxamidine

5-methylthio-4-[(4-phenylphenyl)amino]thiophene-2-carboxamidine

4-[(3-fluoro-4-phenylphenyl)amino]-5-methylthlothiophene-2-carboxamidine

4-(2H-benzo[d]1,3-dioxolen-5-ylamino)-5-methylthiothiophene-2-carboxamidine

4-[(4-butylphenyl)amino]-5-methylthiothiophene-2-carboxamidine

5-methylthio-4-[benzylamino]thiophene-2-carboxamidine

4-(indan-5-ylamino)-5-methylthiothiophene-2-carboxamidine

4-(2,3-dihydrobenzo[b]furan-5-ylamino)-5-methylthiothiophene-2-carboxamidine

5-methylthio-4-[(2-phenylimidazol-4-yl)amino]thiophene-2-carboxamidine

5-methylthio-4-[(2-quinolylmethyl)amino]thiophene-2-carboxamidine

4-{[(3-hydroxyphenyl)methyl]amino}-5-methylthiothiophene-2-carboxamidine

5-methylthio-4-(phenylcarbonylamino)thiophene-2-carboxamidine

4-((2E)-3-phenylprop-2-enoylamino)-5-methylthiothiophene-2-carboxamidine

4-[(4-chlorophenyl)carbonylamino]-5-methylthiothiophene-2-carboxamidine

4-(cyclohexylcarbonylamino)-5-methylthiothiophene-2-carboxamidine methyl4-[(4-methyl-3-nitrophenyl)carbonylamino]-5-methylthiothiophene-2-carboxylate

4-(2-furylcarbonylamino)-5-methylthiothiophene-2-carboxamidine

4-(2,2-dimethylpropanoylamino)-5-methylthiothiophene-2-carboxamidine

4-[5-(3,5-dichlorophenoxy)(2-furyl)]carbonylamino)-5-methylthiothiophene-2-carboxamidine

5-methylthio-4-(naphthylcarbonylamino)-thiophene-2-carboxamidine

5-methylthio-4-(2-quinolylcarbonyl-amino)thiophene-2-carboxamidine

4-[(3-methoxyphenyl)carbonylamino]-5-methylthiothiophene-2-carboxamidine

4-[2-(2-hydroxy-5-methoxyphenyl)acetylamino]-5-methylthiothiophene-2-carboxamidine

4-[(4-ethoxyphenyl)carbonylamino]-5-methylthiothiophene-2-carboxamidine

5-methylthio-4-(2-phenoxyacetylamino)-thiophene-2-carboxamidine

4-[(3-methylphenyl)carbonylamino]-5-methylthiothiophene-2-carboxamidine

5-methylthio-4-[3-(phenylmethoxy)phenyl]amino}thiophene-2-carboxamidine

5-methylthio-4-[(3-phenoxyphenyl) amino)thiophene-2-carboxamidine

5-methylthio-4-[(4-phenoxyphenyl)amino]thiophene-2-carboxamidine

4-[(2-methoxyphenyl)amino]-5-methylthiothlophene-2-carboxamidine

4-[(2-methylphenyl)amino]-5-methylthiothiophene-2-carboxamidine

4-[(3-chlorophenyl)amino]-5-methylthiothiophene-2-carboxamidine

4-(methylphenylamino)-5-methylthiothiophene-2-carboxamidine

5-methyl-4-(phenylamino)thiophene-2-carboxamidine

4-{4-(dimethylamino)phenyl]amino}-5-methylthiothiophene-2-carboxamidine

4-[(4-ethylphenyl)amino) ]-5-methylthiothiophene-2-carboxamidine

5-methylthio-4-{[4-(phenylmethoxy)phenyl]amino}thiophene-2-carboxamidine

5-methylthio-4-{[4-(phenylamino)phenyl]amino}thiophene-2-carboxamidine

4-[(4-methoxyphenyl)amino]-5-methylthiothiophene-2-carboxamidine

4-[(3-fluoro-4-methylphenyl)amino]-5-methylthiothiophene-2-carboxamidine

4-(indan-5-ylamino)-5-methylthiothiophene-2-carboxamidine

4-[(9-ethylcarbazol-3-yl)amino]-5-methylthiothiophene-2-carboxamidine

5-methylthio-4-{[(4-phenylphenyl)sulfonyl]amino}thiophene-2-carboxamidine

4-{bis[(4-phenylphenyl)sulfonyl]amino}-5-methylthiothiophene-2-carboxamidine

5-methylthio-4-[(2-naphthylsulfonyl)-amino]thiophene-2-carboxamidine

4-[bis(2-naphthylsulfonyl)amino]-5-methylthiothiophene-2-carboxamidine

4-{[(6-bromo(2-naphthyl))sulfonyl]amino}-5-methylthiothiophene-2-carboxamidine

4-{bis[(6-bromo(2-naphthyl))sulfonyl]amino}-5-methylthiothiophene-2-carboxamidine

5-methylthio-4-[(naphthylsulfonyl)-amino]thiophene-2-carboxamidine

4-[bis(naphthylsulfonyl)amino]-5-methylthiothiophene-2-carboxamidine

4-{[(2-methylphenyl)sulfonyl]amino}-5-methylthiothiophene-2-carboxamidine

4-{bis[(2-methylphenyl)sulfonyl]amino}-5-methylthiothiophene-2-carboxamidine

4-{[(3-methylphenyl)sulfonyl]amino}-5-methylthiothiophene-2-carboxamidine

4-{bis[(3-methylphenyl)sulfonyl]amino}-5-methylthiothiophene-2-carboxamidine

4-{[(4-methylphenyl)sulfonyl]amino}-5-methylthiothiophene-2-carboxamidine

4-{bis[(4-methylphenyl)sulfonyl]amino}-5-methylthiothiophene-2-carboxamidine

5-methylthio-4-{[benzylsulfonyl]amino}-thiophene-2-carboxamidine

5-methylthio-4-phenoxythiophene-2-carboxamidine

5-methylthio-4-(phenylsulfonyl)thiophene-2-carboxamidine

as well as salts thereof, such as hydrochloride or trifluoracetate saltsand prodrugs thereof.

Methods of Use and Pharmaceutical Compositions

For medicinal use, the pharmaceutically acceptable acid addition salts,those salts in which the anion does not contribute significantly totoxicity or pharmacological activity of the organic cation, arepreferred. The acid addition salts are obtained either by reaction of anorganic base of Formula I with an organic or inorganic acid, preferablyby contact in solution, or by any of the standard methods detailed inthe literature available to any practitioner skilled in the art.Examples of useful organic acids are carboxylic acids such as maleicacid, acetic acid, tartaric acid, propionic acid, fumaric acid,isethionic acid, succinic acid, cyclamic acid, pivalic acid and thelike; useful inorganic acids are hydrohalide acids such as HCl, HBr, HI;sulfuric acid; phosphoric acid and the like. Preferred acids for formingacid addition salts include HCl and acetic acid.

The compounds of the present invention represent a novel class of potentinhibitors of metallo, acid, thiol and serine proteases. Examples of theserine proteases inhibited by compounds within the scope of theinvention include leukocyte neutrophil elastase, a proteolytic enzymeimplicated in the pathogenesis of emphysema; chymotrypsin and trypsin,digestive enzymes; pancreatic elastase, and cathepsin G, achymotrypsin-like protease also associated with leukocytes; thrombin andfactor Xa, proteolytic enzymes in the blood coagulation pathway.Inhibition of thermolysin, a metalloprotease, and pepsin, an acidprotease, are also contemplated uses of compounds of the presentinvention. The compounds of the present invention are preferablyemployed to inhibit trypsin-like proteases.

Compounds of the present invention that inhibit urokinase plasminogenactivator are potentially useful in treating excessive cell growthdisease state. Compounds of the present that inhibit urokinase are,therefore, useful as anti-angiogenic, anti-arthritic, anti-inflammatory,anti-invasive, anti-metastatic, anti-restenotic, anti-osteoporotic,anti-retinopathic (for angiogenesis-dependent retinopathies),contraceptive, and tumoristatic treatment agents. For example, suchtreatment agents are useful in the treatment of a variety of diseasestates, including but not limited to, benign prostatic hypertrophy,prostatic carcinoma, tumor metastasis, restenosis and psoriasis. Alsoprovided are methods to inhibit extracellular proteolysis, methods totreat benign prostatic hypertrophy, prostatic carcinoma, tumormetastasis, restenosis and psoriasis by administering the compound ofFormula I. For their end-use application, the potency and otherbiochemical parameters of the enzyme inhibiting characteristics ofcompounds of the present invention are readily ascertained by standardbiochemical techniques well known in the art. Actual dose ranges forthis application will depend upon the nature and severity of the diseasestate of the patient or animal to be treated as determined by theattending diagnostician. It is to be expected that a general dose rangewill be about 0.01 to 50 mg, preferably 0.1 to about 20 mg per kg perday for an effective therapeutic effect.

An end use application of the compounds that inhibit chymotrypsin andtrypsin is in the treatment of pancreatitis. For their end-useapplication, the potency and other biochemical parameters of theenzyme-inhibiting characteristics of the compounds of the presentinvention is readily ascertained by standard biochemical techniques wellknown in the art. Actual dose ranges for their specific end-useapplication will, of course, depend upon the nature and severity of thedisease state of the patient or animal to be treated, as determined bythe attending diagnostician. It is expected that a useful dose rangewill be about 0.01 to about 50 mg, preferably about 0.1 to about 20 mgper kg per day for an effective therapeutic effect.

Compounds of the present invention that are distinguished by theirability to inhibit either factor Xa or thrombin may be employed for anumber of therapeutic purposes. As factor Xa or thrombin inhibitors,compounds of the present invention inhibit thrombin production.Therefore, these compounds are useful for the treatment or prophylaxisof states characterized by abnormal venous or arterial thrombosisinvolving either thrombin production or action. These states include,but are not limited to, deep vein thrombosis; disseminated intravascularcoagulopathy which occurs during septic shock, viral infections andcancer; myocardial infarction; stroke; coronary artery bypass; fibrinformation in the eye; hip replacement; and thrombus formation resultingfrom either thrombolytic therapy or percutaneous transluminal coronaryangioplasty (PCTA).

By virtue of the effects of both factor Xa and thrombin on a host ofcell types, such as smooth muscle cells, endothelial cells andneutrophils, the compounds of the present invention find additional usein the treatment or prophylaxis of adult respiratory distress syndrome;inflammatory responses; wound healing; reperfusion damage;atherosclerosis; and restenosis following an injury such as balloonangioplasty, atherectomy, and arterial stent placement. The compounds ofthe present invention may be useful in treating neoplasia and metastasisas well as neurodegenerative diseases, such as Alzheimer's disease andParkinson's disease.

When employed as thrombin or factor Xa inhibitors, the compounds of thepresent invention may be administered in an effective amount within thedosage range of about 0.1 to about 500 mg/kg, preferably between 0.1 to30 mg/kg body weight, on a regimen in single or 2-4 divided daily doses.

Human leucocyte elastase is released by polymorphonuclear leukocytes atsites of inflammation and thus is a contributing cause for a number ofdisease states. Compounds of the present invention are expected to havean anti-inflammatory effect useful in the treatment of gout, rheumatoidarthritis and other inflammatory diseases, and in the treatment ofemphysema. The leucocyte elastase inhibitory properties of compounds ofthe present invention are determined by the method described below.Cathepsin G has also been implicated in the disease states of arthritis,gout and emphysema, and in addition, glomerulonephritis and lunginfestations caused by infections in the lung. In their end-useapplication the enzyme inhibitory properties of the compounds of FormulaI is readily ascertained by standard biochemical techniques that arewell-known in the art.

The Cathepsin G inhibitory properties of compounds within the scope ofthe present invention are determined by the following method. Apreparation of partially purified human Cathepsin G is obtained by theprocedure of Baugh et al., Biochemistry 15: 836 (1979). Leukocytegranules are a major source for the preparation of leukocyte elastaseand cathepsin G (chymotrypsin-like activity). Leukocytes are lysed andgranules are isolated. The leukocyte granules are extracted with 0.20 Msodium acetate, pH 4.0, and extracts are dialyzed against 0.05 M Trisbuffer, pH 8.0 containing 0.05 M NaCl overnight at 4° C. A proteinfraction precipitates during dialysis and is isolated by centrifugation.This fraction contains most of the chymotrypsin-like activity ofleukocyte granules. Specific substrates are prepared for each enzyme,namely N-Suc-Ala-Ala-Pro-Val-p-nitroanilide andSuc-Ala-Ala-Pro-Phe-p-nitroanilide. The latter is not hydrolyzed byleukocyte elastase. Enzyme preparations are assayed in 2.00 mL of 0.10 MHepes buffer, pH 7.5, containing 0.50 M NaCl, 10% dimethylsulfoxide and0.0020 M Suc-Ala-Ala-Pro-Phe-p-nitroanilide as a substrate. Hydrolysisof the p-nitroanilide substrate is monitored at 405 nm and at 25° C.

Useful dose range for the application of compounds of the presentinvention as neutrophil elastase inhibitors and as Cathepsin Ginhibitors depend upon the nature and severity of the disease state, asdetermined by the attending diagnostician, with a range of 0.01 to 10mg/kg body weight, per day, being useful for the aforementioned diseasestates.

Additional uses for compounds of the present invention include analysisof commercial reagent enzymes for active site concentration. Forexample, chymotrypsin is supplied as a standard reagent for use inclinical quantitation of chymotrypsin activity in pancreatic juices andfeces. Such assays are diagnostic for gastrointestinal and pancreaticdisorders. Pancreatic elastase is also supplied commercially as areagent for quantitation of α₁-antitrypsin in plasma. Plasmaα₁-antitrypsin increases in concentration during the course of severalinflammatory diseases, and α₁-antitrypsin deficiencies are associatedwith increased incidence of lung disease. Compounds of the presentinvention can be used to enhance the accuracy and reproducibility ofthese assays by titrametric standardization of the commercial elastasesupplied as a reagent. See, U.S. Pat. No. 4,499,082.

Protease activity in certain protein extracts during purification ofparticular proteins is a recurring problem which can complicate andcompromise the results of protein isolation procedures. Certainproteases present in such extracts can be inhibited during purificationsteps by compounds of the present invention, which bind tightly tovarious proteolytic enzymes.

The pharmaceutical compositions of the invention can be administered toany animal that can experience the beneficial effects of the compoundsof the invention. Foremost among such animals are humans, although theinvention is not intended to be so limited.

The pharmaceutical compositions of the present invention can beadministered by any means that achieve their intended purpose. Forexample, administration can be by parenteral, subcutaneous, intravenous,intramuscular, intraperitoneal, transdermal, buccal, or ocular routes.Alternatively, or concurrently, administration can be by the oral route.The dosage administered will be dependent upon the age, health, andweight of the recipient, kind of concurrent treatment, if any, frequencyof treatment, and the nature of the effect desired.

In addition to the pharmacologically active compounds, the newpharmaceutical preparations can contain suitable pharmaceuticallyacceptable carriers comprising excipients and auxiliaries thatfacilitate processing of the active compounds into preparations that canbe used pharmaceutically.

The pharmaceutical preparations of the present invention aremanufactured in a manner that is, itself, known, for example, by meansof conventional mixing, granulating, dragee-making, dissolving, orlyophilizing processes. Thus, pharmaceutical preparations for oral usecan be obtained by combining the active compounds with solid excipients,optionally grinding the resulting mixture and processing the mixture ofgranules, after adding suitable auxiliaries, if desired or necessary, toobtain tablets or dragee cores.

Suitable excipients are, in particular, fillers such as saccharides, forexample, lactose or sucrose, mannitol or sorbitol, cellulosepreparations and/or calcium phosphates, for example, tricalciumphosphate or calcium hydrogen phosphate, as well as binders, such as,starch paste, using, for example, maize starch, wheat starch, ricestarch, potato starch, gelatin, tragacanth, methyl cellulose,hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and/orpolyvinyl pyrrolidone. If desired, disintegrating agents can be added,such as, the above-mentioned starches and also carboxymethyl-starch,cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a saltthereof, such as, sodium alginate. Auxiliaries are, above all,flow-regulating agents and lubricants, for example, silica, talc,stearic acid or salts thereof, such as, magnesium stearate or calciumstearate, and/or polyethylene glycol. Dragee cores are provided withsuitable coatings that, if desired, are resistant to gastric juices. Forthis purpose, concentrated saccharide solutions can be used, which mayoptionally contain gum arabic, talc, polyvinyl pyrrolidone, polyethyleneglycol, and/or titanium dioxide, lacquer solutions and suitable organicsolvents or solvent mixtures. In order to produce coatings resistant togastric juices, solutions of suitable cellulose preparations, such as,acetylcellulose phthalate or hydroxypropylmethyl-cellulose phthalate,are used. Dye stuffs or pigments can be added to the tablets or drageecoatings, for example, for identification or in order to characterizecombinations of active compound doses.

Other pharmaceutical preparations which can be used orally includepush-fit capsules made of gelatin, as well as soft, sealed capsules madeof gelatin and a plasticizer, such as, glycerol or sorbitol. Thepush-fit capsules can contain the active compounds in the form ofgranules that may be mixed with fillers such as lactose, binders such asstarches, and/or lubricants such as talc or magnesium stearate and,optionally, stabilizers. In soft capsules, the active compounds arepreferably dissolved or suspended in suitable liquids, such as, fattyoils or liquid paraffin. In addition, stabilizers may be added.

Suitable formulations for parenteral administration include aqueoussolutions of the active compounds in water-soluble form, for example,water-soluble salts, alkaline solutions and cyclodextrin inclusioncomplexes. Especially preferred salts are hydrochloride and acetatesalts. One or more modified or unmodified cyclodextrins can be employedto stabilize and increase the water solubility of compounds of thepresent invention. Useful cyclodextrins for this purpose are disclosedin U.S. Pat. Nos. 4,727,064, 4,764,604, and 5,024,998.

In addition, suspensions of the active compounds as appropriate oilyinjection suspensions can be administered. Suitable lipophilic solventsor vehicles include fatty oils, for example, sesame oil, or syntheticfatty acid esters, for example, ethyl oleate or triglycerides orpolyethylene glycol-400 (the compounds are soluble in PEG-400). Aqueousinjection suspensions can contain substances that increase the viscosityof the suspension, for example, sodium carboxymethyl cellulose,sorbitol, and/or dextran. Optionally, the suspension may also containstabilizers.

Methods of Making

Many synthetic methods used to form compounds of the present inventiongenerally involve the formation of an amidine from a carboxylic acidderivative, such as an ester or a nitrile. In the process a Lewis acid,such as trimethylaluminum, is added to a source of ammonia, such asammonium chloride in an aprotic solvent, such as a toluene, under aninert atmosphere (e.g., under an atmosphere of nitrogen or argon gas) ata temperature between −15° C. and 5° C., preferably at 0° C. Anappropriate carboxylic acid derivative is added to the mixture and themixture is heated at reflux for a predetermined period of time,preferably between 1 hr. and 24 hrs., and most preferably between 1 hr.and 4 hrs. The resulting solution is allowed to cool to room temperatureand the amidine product isolated by known methods.

Description of Syntheses

The chemical schemes appear after the description of the schemes.

Scheme 1a

Scheme 1a illustrates a general approach to compounds of Formula I whereX=O or S, R³=alkylthio, aralkylthio, arylthio, alkyloxy, aralkyloxy oraryloxy, Y=bond and Z=NR⁵R⁶. When R²² and R²¹ of compounds 2 and 3 areretained in the final product, they correspond to R² and R³ of FormulaI, respectively. Otherwise R²² and R²¹ represent groups which, afterfurther transformations, will become R² and R³ of Formula I.

Starting with the heterocycle where X=O or S appropriately substitutedby two leaving groups, the leaving groups can be sequentially displacedby appropriate nucleophiles (preferably the anion of the group R²¹ orR²² to be substituted) to produce the mono- or disubstitutedheterocycles. Examples of leaving groups include halogens (chlorine,bromine or iodine), sulfonates (methanesulfonate, toluenesulfonate ortrifluoromethanesulfonate) or sulfones (methylsulfonyl). Preferablenucleophiles include anions of thiols or alcohols having as thecounterion an alkali or alkali earth metal such as sodium, lithium,potassium, magnesium or cesium, or in some cases, a transition groupmetal such as zinc, copper or nickel. In certain cases where thenucleophile used contains an anion on carbon, catalysis of thedisplacement may be useful for this transformation. Examples ofcatalysts would include compounds containing palladium, silver or Nisalts.

Scheme 1b

Scheme 1b illustrates approaches to providing the functionality ofY(CNR⁴)Z in compounds of Formula I where X=N, O or S, R²² and R²¹ aredefined as in Scheme 1a. Depending on the nature of the group W in 3,several methods may be employed in the transformation of W to Y(CNR⁴)Z.

When W in 3 is a cyano group (CN), primary amide (CONH₂) or ester(CO₂R²³), direct conversion to an unsubstituted amidine 5 (i.e. FormulaI where Y=bond, Z=NR⁵R⁶ and R⁴, R⁵, R⁶=H) can be effected by treatmentwith a reagent consisting of a Lewis acid complexed to ammonia. Thiscomplex is produced by treatment of ammonia or an ammonium salt,preferably an ammonium halide and most preferably ammonium chloride orbromide, with an appropriate Lewis acid, preferably a trialkylaluminumand most preferably trimethyl- or triethylaluminum in a solvent inert tothe Lewis acid employed. For example, when a trialkylaluminum Lewis acidis employed with an ammonium halide, reaction occurs with loss of oneequivalent of alkane to produce the dialkylhaloaluminum complex ofammonia (see for example Sidler, D. R., et al, J. Org. Chem., 59:1231(1994)). Examples of suitable solvents include unsaturated hydrocarbonssuch as benzene, toluene, xylenes, or mesitylene, preferably toluene, orhalogenated hydrocarbons such as dichloroethane, chlorobenzene ordichlorobenzene. The amidination reaction is generally carried out atelevated temperatures, preferably 40-200 ° C., more preferably 80-140°C., and most preferably at the reflux temperature of a solvent in therange of 80-120° C.

When W is a cyano group (CN), direct conversion to a mono- ordisubstituted amidine 5 (R⁴, R⁵, R⁶=H) is also possible by treatmentwith a reagent consisting of a Lewis acid, preferably atrialkylaluminum, complexed to a mono- or disubstituted amine H₂NR⁵ orHNR⁵R⁶ (Garigipati, R., Tetrahedron Lett. 31: 1969 (1990)).Alternatively the same addition of a mono- or disubstituted amine maycatalyzed by a copper salt such as Cu(I) chloride (Rousselet, G., et al,Tetrahedron Lett. 34: 6395 (1993)).

When W in 3 is a carboxyl group (CO₂H), indirect conversion to anunsubstituted amidine 5 can be carried out by initial esterification to4 by any of a number of well-known dehydrating agents (for example,dicyclohexylcarbodiimide) with an alcohol (R²³OH). More preferably 4 canbe made by initial formation of an acid chloride by treatment of 3 withany of a number of anhydrides of HCl and another acid, such as thionylchloride, POCl₃, PCl₃, PCl₅, or more preferably oxalyl chloride, with orwithout an added catalyst such as N,N-dimethylformamide (DMF), followedby the alcohol R²³OH. Conversion to the unsubstituted amidine 5 (R⁴, R⁵,R⁶=H) can be carried out by treatment with a Lewis acid complexed toammonia.

Amidines 5 also can be produced indirectly by conversion of 3 (W=CN) toiminoethers 6 by exposure to a strong acid such as a hydrogen halide,HBF₄ or other non-nucleophilic acid, preferably gaseous HCl in thepresence of an alcohol R²³OH (R²³=alkyl, branched alkyl or cycloalkyl,preferably Me or Et) and most preferably with the alcohol as solvent.Alternatively when W=CONH₂, conversion to an iminoether can be carriedout by treatment with a trialkyloxonium salt (Meerwein's salts). Ineither case, treatment of the iminoether 6 with ammonia (R⁵, R⁶=H) or amono- or disubstituted amine (HNR5R⁶) provides the correspondingunsubstituted or substituted amidines 5 (i.e. via classical Pinnersynthesis: Pinner, A., Die Iminoaether und ihre Derivate, Verlag R.Oppenheim, Berlin (1892)).

When W=NH₂ in 3, treatment with a reagent Z(CNR⁴)L where Z=alkyl and Lis a leaving group such as O-alkyl and preferably OMe, provides thesubclass of amidines 135 (Z=alkyl ) which are isomeric to 5 (Formula I,where Y=NH, Z=H or alkyl). Examples of reagents for this reactioninclude methyl or ethyl acetimidate hydrochloride. Alternativelytreatment of 3 (W=NH₂) with a trialkyl orthoformate ester, preferablytrimethyl- or triethyl orthoformate, followed by an amine R⁴NH₂ affordsthe corresponding formidines 135 (Z=H) (Formula I, where Y=NH, Z=H).

Also, when W=NH₂, 3 can be treated with a reagent Z(CNR⁴)L where R₄=Hand Z=NR⁵R⁶ and L is a leaving group such as pyrazole, methylpyrazole,SO₃H, S-alkyl, S-aryl, trifluoromethanesulfonate (OTf) ortrifluoromethanesulfonamide (NHTf), preferably pyrazole, SO₃H ortrifluoromethanesulfonamide (NHTf). Examples of these reagents includeaminoiminosulfonic acid (Miller, A. E. and Bischoff, J. J., Synthesis,777 (1986) and 1H-pyrazole-1-carboxamidine hydrochloride (Bernatowicz,M. S., et al., J. Org. Chem. 57:2497 (1992)). Such treatment providesguanidines 136 directly (Formula I where Y=NH, Z=NR⁵R⁶). Alternatively areagent Z(CNP¹)L may be also used where Z=NHP² and L again a leavinggroup such as pyrazole, methylpyrazole, SO₃H, S-alkyl, S-aryl,trifluoromethanesulfonate (OTf) or trifluoromethanesulfonamide (NHTf),to provide protected guanidines (P¹, p²=alkoxylcarbonyl,aralkoxycarbonyl or polymer-bound alkoxylcarbonyl similar to thosedescribed below in Scheme 4a) where the protecting groups P¹ and P² canthen be removed to give unsubstituted 136 (R⁴, R⁵ and R⁶=H). Protectedguanidines are advantageous when further transformations are requiredafter introduction of the guanidine functionality where an unprotectedguanidine would not be stable. Examples of these protected reagentsinclude reagents such as N,N′-bis(tert-butoxycarbonyl)-S-methylthiourea(Bergeron, R. J. and McManis, J. S, J. Org. Chem. 52:1700 (1987)),N,N′-bis(benzyloxycarbonyl)-1H-pyrazole-1-carboxamidine orN,N′-bis(tert-butoxycarbonyl)-1H-pyrazole-1-carboxamidine (Bernatowicz,M. S., et al., Tetrahedron Letters, 34: 3389 (1993)),N,N′-bis(benzyloxycarbonyl)-N″-trifluoromethanesulfonylguanidine, andN,N′-bis(bis(tert-butoxycarbonyl)-N″-trifluoromethanesulfonylguanidine(Feichtinger, K., et al, J. Org. Chem. 63:3804 (1998)). Detaileddescriptions and examples of these protecting groups and their use asprotection for amidines are further outlined in Schemes 4a, 4b and 5.

When W in 3 is an ester (CO₂R²³) or carboxyl group (CO₂H), indirectconversion to an N-substituted or unsubstituted methylarmidine (FormulaI where Y=CH₂, Z=NR⁵R⁶) can be carried out by initial reduction of theester or carboxyl by any of a number of well-known reducing agents. WhenW in 3 is an ester (CO₂R²³), examples of reducing agents includereducing agents such lithium aluminum hydride (LAH) and lithiumborohydride. When W in 3 is a carboxyl group (CO₂H), examples ofreducing agents include LAH and borane complexed to THF, dimethylsulfide, dimethylamine or pyridine. The resulting hydroxymethylderivative (W=CH₂OH) is converted to a cyanomethyl derivative (W=CH₂CN)by initial formation of a leaving group (W=CH₂L) where the leaving groupL is a halogen (chlorine, bromine or iodine) or sulfonate ester (forexample methanesulfonate, toluenesulfonate ortrifluoromethanesulfonate). Displacement of L by cyanide can then beperformed by treatment with a metal cyanide such as LiCN, NaCN, KCN orCuCN in a polar solvent such as DMF and with or without a catalyst suchas a crown ether, to afford the cyanomethyl derivative (see for exampleMizuno, Y., et al, Synthesis, 1008 (1980)). More preferably, theconversion of W=CH₂OH to W=CH₂CN may be effected by a Mitsunobu reaction(Mitsunobu, O., Synthesis, 1 (1981)) using an azodicarboxylate estersuch as diethyl azodicarboxylate or diusopropyl azodicarboxylate, Ph₃Pand a source of cyanide such as HCN or more preferably acetonecyanohydrin (Wilk, B. Synthetic Commun. 23:2481 (1993)). Treatment ofthe resulting cyanomethyl intermediate (W=CH₂CN) under the conditionsdescribed for the conversion of 3 (W=CN) to 5 (either directly orindirectly via 6) provides the corresponding amidinomethyl products.

Scheme 1c

When not commercially available, alkylthiothiophenes (3, X=S, R¹OH orNH₂, R¹²=SR⁵⁴, W=CN, CO₂R²³, CONH₂) can be synthesized by the methodsillustrated in Scheme 1c. Condensation of carbon disulfide and a malonicacid derivative (R⁵²CH₂R²²) in the presence of two alkylating agentsR⁵⁴L and WCH₂L and a base in a suitable medium provide 3 (Dolman, H.,European Patent Application No. 0 234 622 A1 (1987)). When R²²=R⁵²=CN,the resulting R¹ will be NH₂; when R²²=R⁵²=CO₂R²³, the resulting R¹ willbe OH; and when R²² and R⁵²=CN, CO₂R²³, the resulting R¹ can be selectedto be OH or NH₂ (and R²²=CN or CO₂R²³) depending on the reactionconditions and order of reagent addition. Examples of malonic acidderivatives suitable for this transformation include but are not limitedto malonate diesters such as dimethyl malonate or diethyl malonate (R⁵²,R²²=CO₂R²³, R²³=Me or Et), malononitrile (R⁵², R²²=CN), or methyl orethyl cyanoacetate (R⁵²=CO₂R²³, R²²=CN, R²³=Me or Et). Leaving groups Linclude halides such as chloride, bromide or iodide, preferably bromideor iodide, or sulfonates such as toluenesulfonate, benzenesulfonate,methanesulfonate or trifluoromethanesulfonate. Examples of alkylatingagent R⁵⁴L include primary or secondary alkyl, allyl or aralkyl halidesor sulfonates, such as methyl iodide, isopropyl bromide, allyl bromide,benzyl chloride or methyl trifluoromethanesulfonate, or a 2-haloacetateester such as tert-butyl 2-bromoacetate. Examples of alkylating agentsWCH₂L include 2-chloroacetonitrile, methyl 2-bromoacetate or2-bromoacetamide. Suitable media are generally polar aprotic solvents,for example, N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA),N-methylpyrrolidinone (NMP) or dimethylsulfoxide (DMSO), preferably DMF.

Alternatively compounds 3 (R²²=CN) can be synthesized from precursors138 (derived from malononitrile, R⁵⁴L and carbon disulfide), athioglycolate WCHSH and a base in a suitable polar solvent, preferablymethanol (Tominaga, Y., et al, J. Heterocyclic Chem. 31:771 (1994)).

When 3 contains an amino group at R¹, it can be diazotized withsubsequent loss of nitrogen to give 3, R¹=H by treatment with anitrosating agent in suitable solvent. Nitrosating agents includenitrosonium tetrafluoroborate, nitrous acid or, more preferably andalkyl nitrite ester such as tert-butyl nitrite. Suitable solvents arethose which are stable to the nitrosating agents, preferably DMF,benzene or toluene.

Scheme 1d

When not commercially available, heterocyclic precursors 1 or 2 (X=O, S;W=CO₂R²³, COOH; L=halogen) used in Scheme 1a can be synthesized by themethods illustrated in Scheme 1d. Depending on the conditions used,treatment of compounds such as 139 with elemental halogen (Cl₂, Br₂ orI₂, preferably Br₂) or an N-halosuccinimide reagent, preferablyN-bromosuccinimide (NBS), affords either 1 or 2 directly. Description ofsuitable solvents and conditions to selectively produce 1 or 2 are foundin Karminski-Zamola, G. et al, Heterocycles 38:759 (1994); Divald, S.,et al, J. Org. Chem. 41:2835 (1976); and Bury, P., et al, Tetrahedron50:8793 (1994).

Scheme 2a

Scheme 2a illustrates the synthesis of compounds 12 representing thesubclass of compounds for which R² is Formula II, where Ar=2-thiazolyl,Y=bond and Z=NR⁵R⁶. Starting with compound 1 (L=Br) and using thesequential displacement methodology discussed for Scheme 1a, R²¹ can befirst introduced to give 7. This is followed by a second displacementwith a metal cyanide such as copper (I) cyanide, sodium cyanide orlithium cyanide and most preferably copper (I) cyanide at a temperatureof 80-200° C. and preferably at 100-140° C., in a polar aprotic solvent,preferably DMF or DMSO, to give 8. After esterification by any of themeans described for the conversion of 3 to 4, conversion to thethioamide is carried out by treatment of the nitrile with any of themethods well known in the art (see for example Ren, W., et al., J.Heterocyclic Chem. 23:1757 (1986) and Paventi, M. and Edward, J. T.,Can. J. Chem. 65:282 (1987)). A preferable method is treatment of thenitrile with hydrogen sulfide in the presence of a base such as atrialkyl or heterocyclic amine, preferably triethylamine or pyridine, ina polar solvent such as acetone, methanol or DMF and preferablymethanol. Conversion to the thiazole can be executed by classicalHantzsch thiazole synthesis followed by amidine formation as discussedin Scheme 1b.

Scheme 2b

Scheme 2b illustrates the synthesis of compounds representing thesubclass of compounds for which R² is Formula II where, in addition tobeing an alternate route to Ar=2-thiazolyl (20) (see 12, Scheme 2a) alsoprovide compounds of Formula II where Ar=2-oxazolyl (16) or 2-imidazolyl(18) (Y=bond and Z=NR⁵R⁶). Starting with compound 9, a selectivehydrolysis of the nitrile with a tetrahalophthalic acid, preferablytetrafluoro- or tetrachlorophthalic acid, can be used to give 7according to the method of Gribble, G. W. et al., Tetrahedron Lett. 29:6557 (1988). Conversion to the acid chloride can be accomplished usingthe procedures discussed for conversion of 3 to 4, preferably withoxalyl chloride in dichloromethane in the presence of a catalytic amountof DMF. Coupling of the acid chloride to an aminoketone(R²⁶COCH(R²⁷)NH₂) can be performed in the presence of an acid scavenger,preferably N,N-diisopropylethylamine (DIEA) or pyridine in a suitablesolvent such as DMF, dichloromethane or tetrahydrofuran (THF) to affordthe common intermediate 14. Alternatively coupling of the acid chlorideto a less-substituted aminoketone (R²⁶COCH₂NH₂) can be used followed byoptional alkylation with alkylating agent R²⁷L in the presence of abase, preferably NaH or t-BuOK. Transformation of 14 to thecorresponding 2-oxazolyl (15), 2-imidazolyl (17) or 2-thiazolyl (19)esters can carried out by the methodology of Suzuki, M., et al., Chem.Pharm. Bull. 34:3111 (1986) followed by amidination according to Scheme1b. In addition, direct conversion of ketoamide 14 to imidazolylderivative 18 is possible under the same conditions for conversion of 17to 18 when conducted for extended periods, preferably greater than 2 h.

Scheme 2c

Scheme 2c describes a general route to the synthesis of oxazoles,imidazoles and thiazoles of structure 27, 29 and 31 respectively. Acid 2(see Scheme 1a) is converted to the ester by methods that are well knownin the art (Theodora W. Greene and Peter G. M. Wuts, John Wiley andSons, Inc. 1991). For example methyl ester 21 is formed by treating theacid in an appropriate solvent such as methanol withtrimethylsilyldiazomethane. Alternatively the acid is treated withoxalyl chloride and catalytic amounts of dimethylformamide (DMF) in anappropriate solvent such as dichloromethane to form the acid chloride,which is then treated with methanol to give the methyl ester. Ester 21is treated with a palladium (0) catalyst such as palladiumtetrakistriphenylphosphine, and an alkylstannane such ashexa-n-butyldistannane or tri-n-butyltin chloride in an appropriatesolvent such as DMF at elevated temperatures (50° C.-120° C.) to givethe arylstannane of general structure 22 (Stille, J. K., Angew. Chem.Int. Ed. Engl. 25:508-524 (1986)). The stannane 22 is then treated withacid chlorides in the presence of a palladium(0) catalyst to give ketone23. The ketone is treated with ammonia/ammonium chloride to give amine24. Alternatively the ketone is reacted with an azide such as sodiumazide in a suitable solvent such as DMF, and the resulting azidoketoneis reduced to amine 23 with a suitable reducing agent such as catalytichydrogenation in the presence of palladium on carbon and an acid such asHCl (Chem. Pharm. Bull. 33:509-514 (1985)). Ketoamides 25 are formed bycoupling the ketoamine 24 with a variety of suitably functionalized acidchlorides. Alternatively amide coupling may be performed using any of anumber of peptide coupling reagents such as 1,3-dicyclohexylcarbodiimide(Sheehan, J. C. et al., J. Am. Chem. Soc., 77:1067 (1955)) or Castro'sreagent (BOP, Castro, B., et al., Synthesis 413 (1976)). In anotherapproach, amides 25 are formed directly from ketones 23 by reacting withvarious amide salts in an appropriate solvent such as DMF. The amidesalts are generated by treating the amides with a suitable base such assodium hydride (NaH). For example acetamide is treated with NaH in DMFat 0° C. to give sodium acetamide. Keto amide 25 is cyclized to theoxazole 26, imidazole 28 and thiazole 30 using procedures similar tothat shown in scheme 2b. Oxazole 26, imidazole 28 and thiazole 30 aretreated with trimethylaluminum and ammonium chloride in refluxingtoluene to give the amidines 27, 29 and 31 respectively.

Scheme 2d

Scheme 2d illustrates to the preparation of compounds of Examples 42-43,where R²¹ and R⁴³ correspond in Formula I to groups R³ and R²,respectively. The acids 2 can be converted to the stannane by treatmentwith base, such as n-butyl lithium or sec-butyl lithium, followed bytrimethyltin chloride. The resulting acid can be then converted to theester 22 by methods that are well known in the art (Theodora W. Greeneand Peter G. M. Wuts, Protective Groups in Organic Chemistry, John Wileyand Sons, Inc. 1991). For example the methyl ester can be made bytreating the acid 2 in a suitable solvent such as methanol withtrimethylsilyldiazomethane. The stannane 22 can be reacted with suitablehalides in the presence of catalytic amounts of a palladium catalyst,such as palladium tetrakistriphenylphosphine, to give the esters 32(Stille, J. K., Angew. Chem. Int. Ed. Engl. 25:508-524 (1986)). Theseesters are then treated with trimethylaluminum and ammonium chloride inrefluxing toluene to give the amidines 33. In the case where R⁴³L_(n)(n=2), this can be cross-coupled to an aryl, heteroaryl or vinyl boronicacid or ester to give compounds 34 (Miyaura, N. and Suzuki, A., Chem.Rev. 95:2457-2483 (1995)). This can usually be done in the presence ofcatalytic amounts of a palladium (0) catalyst such astetrakistriphenylphosphine palladium and a base such as potassiumcarbonate in DMF at 90° C. Similar cross-coupling reactions can also beachieved by using aryl, heteroaryl and vinyl stannanes instead ofboronic acids or esters. These esters are converted to the amidines 35in the manner previously described.

Scheme 2e

Scheme 2e represents a modification to the methodology outlined inScheme 2b which allows synthesis of compounds of Formula II whereAr=2-thiazolyl, 2-oxazolyl or 2-imidazolyl (Y=bond and Z=NR⁵R⁶) butwhich are regioisomeric to 16, 18 or 20 in the relative positions ofsubstituents R²⁶ and R²⁷. This is illustrated in Scheme 2b by thesynthesis of 2-oxazolyl derivative 39. Thus, acid 13 can be coupled toan hydroxy-containing amine R²⁷CH(NH₂)CH(R²⁶)OH to give amide 36 by anyof a number of amide coupling reagents well known in the art (seeBodanszky, M. and Bodanszky, A., The Practice of Peptide Synthesis,Springer-Verlag, New York (1984)). More preferably 13 can be convertedto the corresponding acid chloride using any of the procedures mentionedfor conversion of 3 to 4 followed by treatment with theR²⁷CH(NH₂)CH(R²⁶)OH in the presence of an acid scavenger, preferablyN,N-diisopropylethylamine (DIEA) or pyridine in a suitable solvent suchas DMF, dichloromethane or tetrahydrofuran (THF) to give 36. Oxidationof the alcohol 36 to the aldehyde 37 (R²⁶=H) or ketone 37 (R²⁶=alkyl,aryl, aralkyl, heterocycle) can be effected by any of a number of commonmethods known in the art (see for example F. Carey, F. A., Sundberg, R.J. Advanced Organic Chemistry, Part B: Reactions and Synthesis, 3rdEdition, Plenum Press, New York (1990)), preferably by a mildMoffatt-type oxidation such as a Swern oxidation (Mancuso, A. J., Huang,S. L. and Swern, D., J. Org. Chem. 3329 (1976)) or more preferably usingDess-Martin reagent (Dess, D. B. and Martin, J. C., J. Org. Chem.48:4155 (1983)). Conversion to the heterocycle (in this case theoxazole) is effected with any of a number of reagents includingphosphorus oxychloride, P₂O₅ or thionyl chloride (see Moriya, T., etal., J. Med. Chem. 31:1197 (1988) and references therein). Alternativelyclosure of 37 with either Burgess reagent or under Mitsunobu conditionsaffords the corresponding oxazolinyl derivatives (Wipf, P. and Miller,C. P., Tetrahedron Lett. 3: 907 (1992)). Final amidination to 39 as inScheme 1b completes the synthesis.

Scheme 2f

Scheme 2f illustrates a general approach to the synthesis of thiazolesof structure 43 (Formula II, X=S, Ar=thiazolyl). Nitriles of structure40 can be treated with hydrogen sulfide (H₂S) in a suitable solvent suchas methanol, or pyridine in the presence of a base such as triethylamineto give thioamides 41 (Ren, W. et al., J. Heterocyclic Chem.23:1757-1763 (1986)). Thioamides 41 can be then treated with varioushaloketones 42 preferably bromoketones under suitable reactionconditions such as refluxing acetone or DMF heated to 50° C.-80° C. toform the thiazoles 43 (Hantzsch, A. R. et al., Ber. 20:3118 (1887)).

Scheme 2g

Scheme 2g illustrates one synthetic route to 2-haloketones of structure42 which are employed in the synthesis of thiazolyl derivatives as inSchemes 2a and 2f. 2-Bromoketones 42 (L=Br) are prepared by treating theketone 44 with a suitable brominating agent such as Br₂ orN-bromosuccinimide in a suitable solvent such as chloroform or aceticacid (EP 0393936 A1).

Alternatively, the ketone 44 is treated with a polymer-supportedbrominating agent such as poly(4-vinyl)pyridinium bromide resin (Sket,B., et al., Synthetic Communications 19:2481-2487 (1989)) to givebromoketones 42. In a similar fashion 2-chloroketones are obtained bytreating 44 with copper (II) chloride in a suitable solvent such aschloroform (Kosower, E. M., et al., J. Org. Chem. 28:630 (1963)).

Scheme 2h

Scheme 2h illustrates another synthetic route to 2-haloketones ofstructure 42 which is particularly useful in that it employs acids 45 oractivated carbonyl compounds such as 46 as precursors which are morereadily available than the ketones 44. The acid 45 is converted to theacid halide 46 (L=Cl, Br or OCOR³⁹) by treating with a suitablehalogenating reagent. For example, an acid chloride is formed bytreating 45 with oxalyl chloride and catalytic amounts of DMF indichloromethane. The acid chloride is converted to a diazoketone bytreatment with trimethysilyldiazomethane (Aoyama, T. et al., TetrahedronLett. 21:4461-4462 (1980)). The resulting diazoketone is converted to a2-haloketone of structure 42 by treatment with a suitable mineral acid.For example a bromoketone is formed by treating the diazoketone in asuitable solvent such as acetonitrile (CH₃CN) with a solution of 30%hydrogen bromide (HBr) in acetic acid (Organic Synthesis Collective VolIII, 119, John Wiley and Sons, New York, Ed. Horning E. C.). In analternative approach the acid 45 is converted to the mixed-anhydride 46by treatment with a suitable chloroformate such as isobutylchloroformate or tert-butyl chloroformate in a suitable solvent, such astetrahydrofuran or dichloromethane, in the presence of a base such asN-methylmorpholine. The mixed anhydride 46 is converted to a diazoketoneby treatment with trimethylsilyldiazomethane and the resultingdiazoketone is converted to a haloketone in the manner described above.

Scheme 2i

When amide coupling as described in Scheme 2e is followed directly byamidination, compounds of Formula I where R² or R³ is aminoacyl oraminoiminomethyl can be derived. Thus, coupling of acid 13 (or thecorresponding acid chloride as previously described) with an amineR⁵¹R⁵²NH can afford 130 which can be carried on to the amidine 131. Uponeither longer or more vigorous additional treatment (for example, highertemperatures) with a Lewis acid-ammonia reagent as described in Scheme1b, the amide group can be converted to an aminoiminomethyl group togive a bisamidine compound 132.

Scheme 3a

Acid 13 can also be converted to an amine 47 from which sulfonamides,ureas and urethanes can be formed (Formula I where R² or R³=NR³²SO₂R³¹,NHCONR⁵¹R⁵² or NHCOR³¹, respectively). Scheme 3a illustrates thismethodology for introduction of these three groups at R² of Formula I.Conversion of the acid 13 to an intermediate acyl azide can be followedby heating of such azide in the presence of an alcohol under Curtiusrearrangement conditions to form the carbamate ester of the alcohol.Subsequent carbamate ester hydrolysis yields amine 47. The intermediateacyl azide may be synthesized by coupling the acid 13 to hydrazinethrough the acid chloride or by any of the amide coupling proceduresdiscussed for Scheme 2e followed by nitrosation of the resultinghydrazide by any of the nitrosating agents discussed for conversion of 3(R¹=NH₂) to 3 (R¹=H) in Scheme 1c. More preferably conversion of 13 to47 is carried out through treatment of acid 13 with diphenylphosphorylazide in the presence of an alcohol, preferably tert-butanol, and abase, preferably triethylamine or DIEA, as shown in Scheme 3a, to give atert-butylcarbamate that is readily decomposed to the salt of amine 47on exposure to an acid, preferably HCl or trifluoroacetic acid in asuitable solvent such as CH₂Cl₂. Further treatment with a base such asNaOH or preferably K₂CO₃ or NaHCO₃ provides the free base 47. Treatmentof amine 47 with a sulfonyl chloride R³¹SO₂Cl in the presence of an acidscavenger, such as pyridine or DIEA, followed by optional alkylation onnitrogen with an alkylating agent R³²L in the presence of a base such asK₂CO₃, DIEA or more preferably sodium hydride, in a solvent such as THF,MeCN or CH₂Cl₂ affords the sulfonylamine functionality at R² (48). Whennecessary, this transformation can be catalyzed by the presence of4-dimethylaminopyridine for less reactive sulfonyl chlorides. Similartreatment of amine 47 with an isocyanate R⁵¹NCO or carbamyl chlorideR⁵¹R⁵²COCl affords the aminocarbonylamine functionality at R² (50).Similar treatment of amine 47 with an acid chloride R³¹COCl affords thecarbonylamine functionality at R² (52). Conversion of the esters in 48,50 and 52 to amidines as previously mentioned gives the products 49, 51and 53. Further conversion of the acylamino group of 53 as discussed forsynthesis of 132 also provides access to the iminomethylamino group atR² (54).

Scheme 3b

Introduction of an aminosulfonyl group (including monoalkylaminosulfonyland dialkylaminosulfonyl groups) for R² of Formula I can be carried outstarting from amine such as 47 as well. Conversion to a sulfonylchloride by the method of Gengnagel, et al. (U.S. Pat. No. 3,947,512(1976)) and treatment with an amine R³⁴NH₂ followed by optionalalkylation on nitrogen with R³⁵L (under the sulfonylation and alkylationconditions described in Scheme 3a) provides 56 which is furtherconverted to amidines 57 as previously described.

Scheme 3c

In addition to the synthesis outlined in Scheme 3a, amine 47 may also beproduced as illustrated in Scheme 3c. A nitrothienyl ester 122(Dell'Erba, C. and Spinelli, D., Tetrahedron, 21: 1061 (1965),Dell'Erba, C. et al., J. Chem. Soc, Perkin Trans 2, 1779 (1989)) with asuitable leaving group L may be substituted with an anion of R²¹ to giveintermediate 123. Amine 47 is then derived from reduction of the nitrogroup. Appropriate reagents to effect reduction of the nitrofunctionality include hydrogen gas in the presence of a catalyst such aspalladium or platinum metal deposited on carbon or barium sulfate in anyof a number of solvents such as methanol, ethanol, ethyl acetate, DMF orTHF. More preferably, tin (II) chloride may be employed as a reductantin solvents such as DMF or THF, or in the presence of HCl in a solventsuch as methanol or ethanol. Alternatively, metals such as zinc or iron(Stanetty, P. and Kremslehner, M., Heterocycles 48: 259 (1998)) may alsobe used.

Scheme 4a

Scheme 4a illustrates the preparation of the compounds of Formula IIIand Examples 48-59 and 61-77. The amidine moiety of compounds ofstructure 60 can be protected with a protecting group P¹ that can bereadily removed from 62 and 64 using methods known to those skilled inthe art (Theodora W. Greene and Peter G. M. Wuts, John Wiley and Sons,Inc. 1991). For example, a tert-butoxycarbonyl (BOC) protecting groupcan be removed by exposure to strongly acidic medium such as hydrogenchloride in a suitable solvent such as dioxane, or by trifluoroaceticacid in a suitable solvent such as methylene chloride. Benzyloxycarbonyl(Cbz) protecting groups can be removed by catalytic hydrogenation usingpalladium on carbon as a catalyst in solvents such as ethanol ortetrahydrofuran.

In some cases, P¹ can be a solid support such as polystyrene orpolyethyleneglycol-grafted polystyrene which can be attached to theamidine moiety via a cleavable linker such as4-(benzyloxy)benzyloxy-carbonyl (using carbonate Wang resin). Attachingan amidine to a solid support can be achieved by treating a solidsupport having a linker containing an appropriately activated functionalgroup with the amidine under suitable conditions. For example, anamidine can be attached to Wang resin by treatingpara-nitrophenylcarbonate Wang resin with the amidine and a suitablebase such as DBU in a suitable solvent such as DMF. When D is OH or SHthe protected amidines 61 can be alkylated with carboxy-protected(protecting group is R³⁶) haloaliphatic acids, such as bromoacetic acidor bromopropionic acid in the presence of a suitable base such as cesiumcarbonate or DIEA, in a suitable solvent such as DMF with heating whennecessary to give compounds of structure 62. When D is NO₂, the nitrogroup can be reduced prior to alkylation using an appropriate reducingagent, such as tin (II) chloride, in a suitable solvent such as DMF, orby catalytic hydrogenation using palladium on carbon as a catalyst insolvents such as ethanol or tetrahydrofuran. Other useful carboxyprotecting groups are well known in the art (Theodora W. Greene andPeter G. M. Wuts, Protective Groups in Organic Chemistry, John Wiley andSons, Inc. 1991). For example, tert-butyl ester can be removed byexposure to strongly acidic medium such as hydrogen chloride in asuitable solvent such as dioxane, or such as trifluoroacetic acid in asuitable solvent such as methylene chloride. Benzyl ester can be removedby catalytic hydrogenation using palladium on carbon as a catalyst insolvents such as ethanol or tetrahydrofuran or by base hydrolysis.

When protecting groups P¹ and R³⁶ in compounds 62 are orthogonal (asdefined by the ability to remove one protecting group preferentially inthe presence of the other), R³⁶ can be preferentially removed to giveacids 63. For example when P¹ is BOC and R³⁶ is OMe, the methyl estercan be removed by treating with a base such as sodium hydroxide in asuitable solvent such as aqueous tetrahydrofuran leaving the BOC groupintact. When protecting groups P¹ and R³⁶ in compounds 62 are notorthogonal, both protecting groups are removed, and the amidine can beprotected with a suitable protecting group such as BOC or a suitablyfunctionalized resin. The protected amidine 63 can be treated withvarious amines under suitable amide coupling conditions, such as in thepresence 1-hydroxy-7-azabenzotriazole (HOAt),O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate (HATU) and DIEA to form amides of structure 64. Theamidine protecting group can be then removed, for example by treatingwith an acid, such as trifluoroacetic acid in a suitable solvent such asmethylene chloride, when a BOC protecting group is employed, to giveamidines 65.

Scheme 4b

Scheme 4b illustrates a specific example which utilizes the methoddescribed in Scheme 4a. The amidine moiety of 66 can be monoprotectedwith a tert-butyloxycarbonyl group. The monoprotected phenoxyamidine 67can be alkylated on the phenolic hydroxy group with an ester of2-bromoacetic acid to give 68. In the case where the ester can beremoved by base, it can be hydrolyzed with aqueous base, such as NaOH,to give the acid 69. This acid can be treated with various amines in thepresence of 1-hydroxy-7-azabenzotriazole (HOAt),O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate (HATU) and DIEA to form amides of structure 70. Theamines are unsubstituted, di- or mono-substituted aliphatic or aromaticamines. In some cases the amines are cyclic-amines such as piperazineand piperidine. The amides 70 are then treated with trifluoroacetic acidto give the amidines 71. In the case where the ester 68 is acid-labile,it can be treated with trifluoroacetic acid to give the amidino-acid 72.This amidine can be loaded on to an insoluble support, such aspolystyrene or polyethyleneglycol-grafted polystyrene via a cleavablelinker, such as Wang, which is functionalized as an activated carbonatesuch as p-nitrophenylcarbonate or succinimidyl carbonate. Generally thiscan be done by treating the activated carbonate resin with the amidineand a suitable base such as DBU in a suitable solvent such as DMF. Thesupport-bound acid 73 can be treated with various amines in the presenceof 1-hydroxy-7-azabenzotriazole (HOAt),O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate (HATU) and DIEA to form amides. These amides arethen cleaved from the solid support by treating with trifluoroaceticacid to give compounds of structure 71.

Scheme 5

Scheme 5 illustrates a synthetic route to amidines containingdi-substituted thiazoles represented by compounds for which R² isFormula II and both R⁸ and R⁹ are non-hydrogen substituents. Theketoamide 74 can be converted to the mono-bromoketoamide by treatingwith bromine in acetic acid. Thiazoles 76 are formed by reacting thebromoketoamide with 10 under suitable conditions, preferably by heatingthe mixture in DMF or acetone. Amidines 77 are formed by heating 76 intoluene with trimethylaluminum and ammonium chloride. The amidines 77are treated with strong acid such as HCl to give the acids 78. Theamidines 78 are in one route protected with a suitable protecting groupsuch as BOC to give 79. The protected amidines 79 are treated withvarious amines under suitable coupling conditions, such as in thepresence of HOAt, HATU, and DIEA to form various amides. The amidineprotecting group can be then removed, for example by treating withtrifluoroacetic acid in a suitable solvent such as methylene chloride,when a BOC protecting group is employed to give amidines 80. In a secondroute, the amidines 78 can be loaded onto an insoluble support, such aspolystyrene or polyethyleneglycol-grafted polystyrene via a cleaveablelinker, such as Wang resin, which is functionalized as an activatedcarbonate ester, such as p-nitrophenylcarbonate or succinimidylcarbonate, to give a resin-bound scaffold 81. The resin-bound acid 81can be treated with various amines under suitable coupling conditionssuch as in the presence of HOAT, HATU and DIEA to form amides. Theseamides are then cleaved from the solid support by treating withtrifluoroacetic acid to give amidines 80.

Scheme 6a

Scheme 6a illustrates the preparation of compounds of Examples 144, 145,146, 147, 148, 149, 150 and 151. Compounds of this invention correspondto those of Formula I where R² is Formula II and where Ar is thiazoleand R³⁷ and R³⁸ (R⁸ and R⁹ of Formula II) are phenyl, which can beadditionally substituted. Starting from 2,5-dibromothiophene 90,treatment with lithium diisopropylamide followed by R²¹L, where L is aleaving group, preferably a halogen, mesylate, tosylate, or methylsulfate, and more preferably iodomethane or methyl sulfate, according tothe procedure of Kano, et al., Heterocycles 20(10):2035 (1983), gives91. Compound 91 can be treated with an appropriate base, preferably alithium alkyl like n-butyllithium, sec-butyllithium, or t-butyllithium,and more preferably n-butyllithium, followed by carbon dioxide gas andconversion of the resulting carboxylate salt to the free acid with amineral acid, preferably hydrochloric acid. Conversion to ester 21 canbe carried out by preparation of the acid chloride using oxalyl chlorideand treatment of this intermediate acid chloride with an alcohol R²³ inan appropriate solvent, preferably dichloromethane, with an appropriatebase, preferably pyridine. Compound 21 can be treated with copper (I)cyanide in refluxing dimethylformamide to give compound 9. Compound 9can be treated with hydrogen sulfide gas in an appropriate solvent,preferably methanol, containing an appropriate base, preferablytriethylamine to give compound 10. Compound 10 can be treated with anappropriate ketone where L is a leaving group, preferably halogen,mesyl, or tosyl, and most preferably bromo, refluxing in a suitablesolvent, preferably, acetone, dimethylformamide, dimethyl acetamide,methyl ethyl ketone, or other polar aprotic solvents, and mostpreferably acetone to give compound 92. Compound 92 is treated with anappropriate reagent, preferably the aluminum amide reagent to giveamidine 93.

Scheme 6b

Scheme 6b illustrates the preparation of the compound of Example 144,which corresponds to a compound for which R² is Formula II, and where Aris thiazole and R⁸ and R⁹ (R³⁷ and R³⁸ in Scheme 6b) are phenyl, whichcan be optionally substituted. Starting from 2,5-dibromothiophene 90,treatment with n-butyllithium produces an anion which undergoes arearrangement (Kano, S., et al, Heterocycles 20:2035 (1983)). Quenchingwith carbon dioxide gas and conversion of the resulting carboxylate saltto the free acid with a mineral acid, preferably hydrochloric acid,gives acid 94. Conversion to ester 95 can be carried out by preparationof the acid chloride using oxalyl chloride and treatment of thisintermediate acid chloride with an alcohol R²³—OH in an appropriatesolvent, preferably dichloromethane, with an appropriate base,preferably pyridine. Compound 95 can be treated with copper (1) cyanidein refluxing dimethylformamide to give compound 96. Compound 96 can betreated with hydrogen sulfide gas in an appropriate solvent, preferablymethanol, containing an appropriate base, preferably triethylamine togive compound 97. Compound 97 can be treated with an appropriate ketonewhere L is a leaving group, preferably halogen, mesyl, or tosyl, andmost preferably bromo, refluxing in a suitable solvent, preferably,acetone, dimethylformamide, dimethyl acetamide, methyl ethyl ketone, orother polar aprotic solvents, and most preferably acetone to givecompound 98. Compound 98 is treated with an appropriate reagent,preferably the aluminum amide reagent (Al(CH₃)₃/NH₄Cl) to give amidine99.

Scheme 7a

Scheme 7a illustrates the preparation of compounds for which R² isFormula II and Ar is thiazol-4-yl. As illustrated, the acids 13 can beconverted to their acid chlorides by treatment with oxalyl chloride withdimethylformamide catalysis in methylene chloride, or by using thionylchloride, either neat or in an organic solvent, at ambient or elevatedtemperature. Compounds are then homologated to the desired a-haloketones100 by sequential treatment with trimethylsilyldiazomethane and hydrogenbromide. An alternative would be to substitute diazomethane (generatedfrom Diazald®, Aldrich Chemical Co., Milwaukee, Wis.) for thetrimethylsilyldiazomethane. Also, the conversion of 13 to 100 can beeffected using the procedure derived for the synthesis of compound 42from compound 46.

The alpha-haloketones 100 are then allowed to react with the appropriatethiourea (Scheme 7b) or thioamide derivative in an organic solvent,preferably acetone or dimethylformamide at 70° C. to give2-aminothiazoles or thiazoles 101.

The thiazoles 101 can be treated with the aluminum amine reagent(Al(CH₃)₃/NH₄Cl) formed at ambient temperature by the reaction oftrimethylaluminum with ammonium chloride in an organic solvent,preferably toluene. The ester can then be converted to the amidines 102at elevated temperatures, preferably higher than 80° C.

Scheme 7b

As shown in Scheme 7b, amines 110 (or their hydrochloride salts) can beconverted to their respective mono-substituted thioureas(methan-1-thiones) 112 by treatment with thiophosgene to form theintermediate isothiocyanates 111. Preferred conditions include treatingthe amine with thiophosgene in a biphasic solvent system composed of ahalogenated solvent such as chloroform and an aqueous phase of saturatedsodium bicarbonate. Alternatively, the reaction may be effected bytreatment of 110 with a hindered amine and thiophosgene such astriethylamine or diisopropylethylamine in an organic solvent such astetrahydrofuran or methylene chloride. Another alternative to formingisothiocyanates 111 is the direct treatment of primary amines and carbondisulfide in pyridine with dicyclohexylcarbodiimide (Jochims, Chem. Ber.101:1746 (1968)).

Isothiocyanates 111 can be converted to thioureas 112 by treatment withan ammonia-alcohol solution, preferably a 2M ammonia in methanol orethanol solution, at room temperature or elevated temperatures (>70°C.). Alternatively, the thioureas 112 can be prepared directly form theappropriate urea (or thioamide from the appropriate amide when R⁸=alkylor aryl)) by treatment with Lawesson's reagent (Lawesson, S.-O., et. al.Bull. Soc. Chim. Belg. 87:223, 293 (1978)).

Scheme 8

Scheme 8 illustrates the preparation of compounds of this inventionwhere R² is Formula II and Ar is thiazole and R³⁷ and R³⁸ are phenylwhich is further substituted by a sulfonylamino or carbonylamino group.Starting from thioamide 10, treatment with a nitro substituted2-halo-acetophenone, where the halogen is chloro, bromo, or iodo,preferably bromo, refluxing in a suitable solvent, preferably acetone,dimethylformamide, dimethyl acetamide, methyl ethyl ketone, or otherpolar aprotic solvents, and most preferably acetone. The reduction ofnitroaryl compound 113 can be carried out with a suitable reducingagent, preferably tin (II) chloride, titanium (II) chloride, iron (III)chloride, lithium metal, sodium metal, catalytic hydrogenation overplatinum or palladium catalyst, and most preferably 20% aqueous solutionof titanium (III) chloride. The acylation of aniline 114 can be carriedout with an appropriate acyl compound R⁴²L where L is a halogen,preferably chloro, in an appropriate solvent, preferablydichloromethane, containing a base, preferably pyridine,N-methylmorpholine, or diisopropylethylamine. Alternatively, theacylation of aniline 114 is carried out with an activated carboxylicacid compound R⁴²COL where L is hydroxy activated withdicyclohexylcarbodiimide, ethyl-3-(diethylamino)propylcarbodiimide(EDAC), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU), or pentafluorophenyl. The sulfonylation ofaniline 114 can be carried out with and appropriate sulfonyl chloridecompound R⁴¹SO₂L in an appropriate solvent, preferably dichloromethane,containing a base, preferably N-methyl morpholine,diisopropylethylamine, or pyridine, most preferably N-methyl morpholine,with or without a condensation catalyst, preferabledimethylaminopyridine (DMAP). The amidinylation of compounds 115 and 117can be carried out with an appropriate reagent, preferably the aluminumamide reagent (Al(CH₃)₃/NH₄Cl)

Scheme 9

Scheme 9 illustrates the preparation of compounds of Formula I, forwhich one of R⁵ and R⁶ is a non-hydrogen substituent. The amidines 5 areconverted to the amidoximes 119 by heating with hydroxylamine in asuitable solvent such as ethanol. The cyanoamidines 120 are prepared byheating the amidines 5 with cyanamide in a suitable solvent such asethanol. (Huffman, K. R. and Schaeffer, F., J. Amer. Chem. Soc. 28:1812(1963). Alternatively 5 can be heated with an amine such as methylamineto give the N-alkylated amidines 121.

Scheme 10

Scheme 10 illustrates an approach to compounds of Formula I where X=S orO, R²=arylamino, R³=alkylthio, aralkylthio, arylthio, alkyloxy,aralkyloxy, aryloxy, alkylamino, dialkylamino, aralkylamino,diaralkylamino, arylamino or diarylamino, Y=bond and Z=NR⁵R⁶.

Aminothiophenes 47 (Formula I where X=S, or O; R²=NH₂) can be reactedwith an arylboronic acid (R⁵⁶B(OR⁵⁸)₂, R⁵⁸=H) or arylboronic ester(R⁵⁶B(OR⁵⁸)₂, R⁵⁸=alkyl) in the presence of a copper catalyst,preferably copper (II) acetate, and an amine base such as triethylamineor pyridine (Chan, D. M. T. et al., Tetrahedron Lett 39: 2933 (1998)) togive a thienylarylamine 124. Conversion of the ester to amidine 125 iscarried out in the manner previously described in Scheme 1b.

Scheme 11

Another route to compounds of this invention, where R²=arylamino oralkylarylamino and alkylamino and where R³, Y and Z are as described inScheme 10, is shown in Scheme 11 where intermediate 2 (R²¹=R³, L=leavinggroup) is aminated using conditions well known in the art. (See forexample: Ahman, J. and Buchwald, S. L., Tetrahedron Lett. 38: 6363(1997) and Wolfe, J. P. and Buchwald, S. L., Tetrahedron Lett. 38: 6359(1997). For reviews see: Frost, C. G and Mendonca, P., J. Chem. Soc,Perkin Trans 1: 2615 (1998) and Wolfe, J. P. et al., Acc. Chem. Res. 31:805 (1998).) Thus, 2 may be treated with an aniline R⁵⁶R⁵⁷NH (R⁵⁶=aryl,R⁵⁷=H or alkyl) in the presence of a palladium catalyst, a suitablepalladium ligand and a base to give 127. Suitable catalysts include anyof a number of Pd(0) or Pd(II) salts, such astetrakis(triphenylphosphino) palladium (0),dichlorobis(acetonitrile)palladium (II) or preferably palladium (II)acetate or tris(dibenzylideneacetone)dipalladium. The most appropriateligands for any given reaction are often compound-dependent and arediscussed in detail in the aforementioned references but may include1,1′-bis(diphenylphosphino)ferrocene (DPPF),1-[2-(diphenylphosphino)ferrocenyl]ethyl methyl ether (PPF-OMe), orpreferably 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP).Appropriate bases include sodium t-butoxide or preferably cesiumcarbonate or potassium phoshate. Useful solvents include DMF, dioxane,dimethoxyethane or preferably toluene. Conversion of the ester toamidine 128 is carried out in the manner previously described in Scheme1b.

Scheme 12

The corresponding compounds of Formula I where R²=alkylamino and R³, Yand Z are as described in Scheme 10 are produced as shown in Scheme 12by initial reductive alkylation of amine 47 with an aldehyde R⁵⁹CHO orketone R⁵⁹COR⁶⁰ in the presence of any of a number of suitable reducingagents including sodium borohydride, sodium cyanoborohydride or, morepreferably, sodium or tetraalkylammonium salts of triacetoxyborohydrideto give 129. Depending on the reducing agent employed, suitable solventsmay include an alcohol, such as methanol, ethanol or isopropanol, orsolvents such as THF or dichloromethane. Conversion of the ester to theamidine 130 is again carried out in the manner previously described inScheme 1b.

Scheme 13

Scheme 13 illustrates an approach to compounds of Formula I where R² isa 2-thiazolylamino and R³, Y and Z are as described in Scheme 10. Inthis method, amine 47 can be first converted to a thiourea 131 using thevarious procedures outlined in Scheme 7b. Further reaction of thethiourea with a leaving group-substituted ketone R³⁷COCH(L)R³⁸,preferably a 2-haloketone as described in Schemes 2f, 2g or 2h, canprovide thiazolylaminothiophenes 132 which are then converted to thecorresponding amidines 133 by the previously described methodology ofScheme 1b.

EXAMPLE 14-[4-(4-Chlorophenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxamidine

Trimethylaluminum (2.0 M in toluene, 2 mL) was added dropwise over 10min to a suspension of ammonium chloride (216 mg) in toluene (2 mL),stirred under N₂ at 0° C. When gas evolution moderated, the mixture wasstirred at 25° C. for 30 min, when most of the solid had dissolved,methyl4-[4-(4-chlorophenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxylate(100 mg, Maybridge Chemical Co., Cornwall, U. K.) was added in oneportion. This solution was heated to reflux in stages over 1 h. After2.5 h of reflux, the reaction mixture was allowed to cool to 25° C., andwas poured on to a vigorously stirred slurry of silica gel (2 g) inCHCl₃ (20 mL). After 20 min the solids were collected by suctionfiltration, and washed with MeOH (3×10 mL). The combined filtrates wereevaporated to dryness, and the residual yellow solid was subjected topreparative thin-layer chromatography to obtain 77 mg of4-[(4-chlorophenyl)thiazol-2-yl]-5-methylthiothiophene-2-carboxamidineas a yellow solid. ¹H-NMR (DMSO-d₆; 300 MHz) δ 2.80 (s, 3H), 7.55-7.59(m, 1H), 8.04-8.13 (m, 1H), 8.31 (s, 1H), 8.69 (s, 1H), ), 9.2 (broad s,4H). Mass spectrum (MALDI-TOF, m/z): Calcd. for C₁₅H₁₂ClN₃S₃, 365.9(M+H), found 366.9.

EXAMPLE 2 5-Methylthiothiophene-2-carboxamidine

5-(Methylthio)thiophene-2-carbonitrile (100 mg, Maybridge ChemicalCompany, Cornwall, UK) was taken in a dry 2 dram vial. To this asolution of saturated HCl in anhydrous MeOH (4 mL) was added. The vialwas tightly capped and the mixture was stirred for 24 h. The vial wascooled in an ice bath, uncapped and N₂ was bubbled through the solutionto remove dissolved HCl. The solvent was removed under reduced pressureand the resulting residue was dried under high vacuum for 24 h. Asolution of methanolic ammonia (2M NH₃ in MeOH) was added to the vial,and the mixture was stirred for 3 days. Methanol was removed undervacuum and the resulting residue was subjected to preparative thin-layerchromatography to obtain 5-(methylthio)thiophene-2-carboxamidine as ayellow solid. ¹H-NMR (DMSO-d₆; 300 MHz) δ 2.64 (s, 3H), 7.22 (d, J=3.8Hz, 1H), 7.95 (broad d, J=3.33 Hz, 1H), 9.4 (broad s, 4H). Mass spectrum(MALDI-TOF, m/z): Calcd. for C₆H₈N₂S₂, 172.3 (M+H), found 173.0.

EXAMPLE 3 5-Methylthio-4-phenylthiophene-2-carboxamidine

Methyl 5-methylthio-4-phenylthiophene-2-carboxylate (100 mg, MaybridgeChemical Company, Cornwall, UK) was treated in a manner similar to thatfor Example 1, to give 50 mg of4-phenyl-5-methylthiothiophene-2-carboxamidine as an off-white solid.¹H-NMR (DMSO-d₆; 300 MHz) δ 2.65 (s, 3H), 7.39-7.60 (m, 5H), 8.27 (s,1H), 9.2 (broad s, 4H). Mass spectrum (MALDI-TOF, m/z): Calcd. forC₁₂H₁₂N₂S₂, 248.4 (M+H), found 249.0.

EXAMPLE 44-[4-(2,4-Dichlorophenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxamidine

Methyl4-[4-(2,4-dichlorophenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxylate(100 mg, Maybridge Chemical Company, Cornwall, UK) was treated in amanner similar to that for Example 1, to give 60 mg of4-[4-(2,4-dichlorophenyl)thiazol-2-yl]-5-methylthiothiophene-2-carboxamidineas a yellow solid. ¹H-NMR (DMSO-d₆; 300 MHz) δ 2.77 (s, 3H), 7.6 (dd,J=2.2 and 8.5 Hz, 1H), 7.79 (d, J=2.2 Hz, 1H), 8.09 (d, J=8.5 Hz, 1H),8.3 (s, 1H), 8.6 (s, 1H). Mass spectrum (MALDI-TOF, m/z): Calcd. forC₁₅H₁₁N₃S₃Cl₂, 400.0 (M+H), found 400.1.

EXAMPLE 54-(4-Methyl(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxamidine

Methyl4-(4-methyl(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxylate (100mg, Maybridge Chemical Company, Cornwall, UK) was treated in a mannersimilar to that for Example 1, to give 40 mg of4-(4-methylthiazol-2-yl)-5-methylthiothiophene-2-carboxamidine as ayellow solid. ¹H-NMR (DMSO-d₆; 300 MHz) δ 2.43 (s, 3H), 2.7 (s, 3H),7.38 (s, 1H), 8.28 (s, 1H). Mass spectrum (MALDI-TOF, m/z): Calcd. forC₁₀H₁₁N₃S₃, 270.0 (M+H), found 270.1.

EXAMPLE 6

a) Methyl5-methylthio-4-(4-(2-naphthyl)(1,3-thiazol-2-yl))thiophene-2-carboxylate:Methyl 4-(aminothioxomethyl)-5-methylthiothiophene-2-carboxylate (40 mg,Maybridge Chemical Company, Cornwall, UK) was reacted with2-bromo-2′-acetonaphthone (1.1 eq) in a manner similar to Example 13step (a) to give 40 mg of methyl5-methylthio-4-(4-(2-naphthyl)(1,3-thiazol-2-yl))thiophene-2-carboxylate.¹H-NMR (CDCl₃/CD₃OD; 300 MHz) δ 3.71 (s, 3H), 3.94 (s, 3H), 7.47-7.55(m, 2H), 7.67 (s, 1H), 7.84-7.99 (m, 3H), 8.08 (dd, J=1.75 Hz and 8.6Hz, 1H), 8.3 (s, 1H), 8.5 (s, 1H).

b)5-Methylthio-4-(4-(2-naphthyl)(1,3-thiazol-2-yl))thiophene-2-carboxamidine:Methyl5-methylthio-4-(4-(2-naphthyl)(1,3-thiazol-2-yl))thiophene-2-carboxylate,(40 mg) as prepared in the previous step was treated in a manner similarto that for Example 1, to give 30 mg of4-[4-(naphth-2-yl)thiazol-2-yl]-5-methylthiothiophene-2-carboxamidine.¹H-NMR (DMSO-d₆; 300 MHz) δ 2.83 (s, 3H), 7.52-7.69 (m, 2H), 7.95-8.01(m, 2H), 8.05 (d, J=8.6 Hz, 1H), 8.24 (dd, J=1.69 Hz and 8.6 Hz, 1H),8.4 (s, 1H), 8.65 (s, 1H), 8.74 (s, 1H). Mass spectrum (MALDI-TOF, CHCAmatrix, m/z): Calcd. for C₁₉H₁₅N₃S₃, 382.1 (M+H), found 382.0.

EXAMPLE 75-Methylthio-4-[4-(4-phenylphenyl)(1,3-thiazol-2-yl)/thiophene-2-carboxamidinehydrochloride

a) Methyl5-methylthio-4-[4-(4-phenylphenyl)(1,3-thiazol-2-yl)]thiophene-2-carboxylate:27 mg (0.109 mmol) of methyl4-(aminothioxomethyl)-5-methylthiothiophene-2-carboxylate (MaybridgeChemical Co. LTD., Cornwall, U.K.) was dissolved in 2 mL of reagentgrade acetone. 4′-Phenyl-2-bromoacetophenone (33 mg; 0.120 mmol; AldrichChemical Co., Milwaukee, Wis.) was added and the solution was allowed toreflux for 2.5 h. The solution was allowed to cool and solid wasfiltered and washed with methanol and dried in vacuo to afford 30 mg(65% yield) of methyl5-methylthio-4-[4-(4-phenylphenyl)(1,3-thiazol-2-yl)]thiophene-2-carboxylate.¹H-NMR (DMSO-d₆, 300 MHz) δ 8.28 (s, 1H), 8.24 (s, 1H), 8.17 (d, J=8.5Hz, 2H), 7.8 (d, J=8.5Hz, 2H), 7.74-7.77 (m, 2H), 7.48-7.53 (m, 2H),7.40 (m, 1H), 2.78 (s, 3H). Mass Spectrum (MALDI-TOF, CHCA matrix, m/z)Calcd. for C₂₂H₁₆NO₂S₃: 423.0 (M+H), found 424.4.

b)5-Methylthio-4-[4-(4-phenylphenyl)(1,3-thiazol-2-yl)]thiophene-2-carboxamidinehydrochloride: To a stirred suspension of 0.473 mmol (25 mg) of ammoniumchloride (Fisher Scientific Pittsburgh, Pa.) in 2 mL of anhydroustoluene (Aldrich Chemical Co.) placed under nitrogen atmosphere at 0°C., 237 μL (0.473 mmol) of 2M trimethylaluminum in toluene (AldrichChemical Co.) was added via syringe over 10 min and then let stir at 0°C. for 30 min after which 20 mg (0.0473 mmol) of methyl5-methylthio-4-[4-(4-phenylphenyl)(1,3-thiazol-2-yl)]thiophene-2-carboxylatewas added to solution and allowed to reflux for 2.5 h. The reactionmixture was quenched by pouring over a slurry of 500 mg of silica in 10mL of chloroform. The silica was poured onto a sintered glass funnel andwashed with a 10% methanol/CH₂Cl₂ solution and concentrated. The crudeproduct was purified on a 1 mm silica prep plate eluting with 10%methanol/CH₂Cl₂ to afford 10 mg (53% yield) of5-methylthio-4-[4-(4-phenylphenyl)(1,3-thiazol-2-yl)]thiophene-2-carboxamidinehydrochloride. Mass Spectrum (MALDI-TOF, CHCA matrix, m/z) Calcd. forC₂₁H₁₇N₃S₃: 408.1 (M+H), found 408.0.

EXAMPLES 8 & 94-[4-(3-Methoxyphenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxamidineHydrochloride and4-[4-(3-Hydroxyphenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxamidineHydrochloride

a) Methyl4-[4-(3-methoxyphenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxylate:32 mg (0.133 mmol) of methyl4-(aminothioxomethyl)-5-methylthiothiophene-2-carboxylate (MaybridgeChemical Co. LTD., Cornwall, U.K.) was dissolved in 2 mL of reagentgrade acetone. 3′-Methoxy-2-bromo acetophenone (0.155 mmol; 36 mg;Aldrich Chemical Co.) was added and the solution was allowed to refluxfor 2.5 h The solution was allowed to cool and a solid was filtered andwashed with methanol and dried in vacuo. The solid was purified on 1 mmsilica plate eluting with 25% ethyl acetate/hexane to afford 31 mg (63%yield) of methyl4-[4-(3-methoxyphenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxylate.

b)4-[4-(3-Methoxyphenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxamidinehydrochloride and4-[4-(3-hydroxyphenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxamidinehydrochloride: To a stirred suspension of 0.821 mmol (44 mg) of ammoniumchloride (Fisher Scientific) in 2 mL of anhydrous toluene (AldrichChemical Co.) placed under nitrogen atmosphere at 0° C., was added 411μL (0.821 mmol) of 2M trimethylaluminum in toluene (Aldrich ChemicalCo.) via syringe over 10 min and then let stir at 0° C. for 30 min afterwhich 31 mg (0.0821 mmol) of methyl4-[4-(3-methoxyphenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxylatewas added to solution and allowed to reflux for 2.5 h. The reactionmixture was quenched by pouring over a slurry of 500 mg of silica in 10mL of chloroform. The silica was poured onto a sintered glass funnel andwashed with a 10% methanol/CH₂Cl₂ solution and concentrated. The crudeproduct was purified on a 1 mm silica prep plate eluting with 10%methanol/CH₂Cl₂ to afford 4.4 mg (15% yield) of4-[4-(3-methoxyphenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxamidinehydrochloride and 4.2 mg (15% yield) of4-[4-(3-hydroxyphenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxamidinehydrochloride.4-[4-(3-methoxyphenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxamidinehydrochloride: ¹H-NMR (CD₃OD; 300 MHz) δ 8.5 (s, 1H), 7.9 (s, 1H),7.59-7.65 (m, 2H), 7.33-7.38 (m, 1H), 6.91-6.95 (m, 1H), 3.87 (s, 1H),2.8 (s, 3H) Mass Spectrum (MALDI-TOF, CHCA matrix, m/z) Calcd. forC₁₆H₁₅N₃OS₃: 361.5(M+H), found 362.2.4-[4-(3-hydroxyphenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxamidinehydrochloride: ¹H-NMR (CD₃OD; 300 MHz) δ 8.50 (s, 1H), 7.81 (s, 1H),7.26-7.51 (m, 2H), 7.24 (m, 1H), 6.79 (m, 1H), 2.8 (s, 3H) Mass Spectrum(MALDI-TOF, CHCA matrix, m/z) Calcd. for C₁₅H₁₃N₃OS₃: 347.5(M+H), found348.0.

EXAMPLE 105-Methylthio-4-(4-phenyl(1,3-thiazol-2-yl))thiophene-2-carboxamidineHydrochloride

a) Methyl5-methylthio-4-(4-phenyl(1,3-thiazol-2-yl))thiophene-2-carboxylate: 33mg (0.133 mmol) methyl4-(aminothioxomethyl)-5-methylthiothiophene-2-carboxylate (MaybridgeChemical Co. LTD., Cornwall, U.K.) was dissolved in 2 mL of reagentgrade acetone. 2-Bromoacetophenone (0.133 mmol; 27 mg; Aldrich ChemicalCo.) was added and the solution was allowed to reflux for 2.5 h. Thesolution was allowed to cool and the solid was filtered and washed withmethanol and dried in vacuo. The solid was purified on 1 mm silica plateeluting with 25% ethyl acetate/hexane mixture to afford 46 mg (90%yield) of methyl5-methylthio-4-(4-phenyl(1,3-thiazol-2-yl))thiophene-2-carboxylate.

b) 5-Methylthio-4-(4-phenyl(1,3-thiazol-2-yl))thiophene-2-carboxamidinehydrochloride: To a stirred suspension of 1.32 mmol (71 mg) of ammoniumchloride (Fisher Scientific) in 2 mL of anhydrous toluene (AldrichChemical Co.) placed under nitrogen atmosphere at 0° C., 662 μL (1.32mmol) of 2M trimethylaluminum in toluene (Aldrich Chemical Co.) wasadded via syringe over 10 min and then let stir at 0° C. for 30 minafter which 46 mg (0.133 mmol) of methyl5-methylthio-4-(4-phenyl(1,3-thiazol-2-yl))thiophene-2-carboxylate wasadded to solution and allowed to reflux for 2.5 h. The reaction mixturewas quenched by pouring over a slurry of 500 mg of silica in 10 mL ofchloroform. The silica was poured onto a sintered glass funnel andwashed with a 10% methanol/CH₂Cl₂ solution and concentrated. The crudeproduct was purified on a 2 g silica silica SPE column eluting with 10%methanol/CH₂Cl₂ to afford 32.5 mg (75% yield) of5-methylthio-4-(4-phenyl(1,3-thiazol-2-yl))thiophene-2-carboxamidinehydrochloride. ¹H-NMR (DMSO-d₆; 300 MHz) δ 8.70 (s, 1H), 8.25 (s, 1H),8.07-8.11 (m, 2H), 7.37-7.53 (m, 3H), 2.8 (s, 3H). Mass Spectrum(MALDI-TOF, CHCA matrix, n/z) Calcd. for C₁₅H₁₃N₃S₃: 331.5(M+H), found332.1.

EXAMPLE 115-Methylthio-4-[4-(4-nitrophenyl)(1,3-thiazol-2-yl)]thiophene-2-carboxamidineHydrochloride

a) Methyl5-methylthio-4-[4-(4-nitrophenyl)(1,3-thiazol-2-yl)]thiophene-2-carboxylate:38 mg (0.141 mmol) of methyl4-(aminothioxomethyl)-5-methylthiothiophene-2-carboxylate (MaybridgeChemical Co. LTD., Cornwall, U.K.) was dissolved in 2 mL of reagentgrade acetone. 2-Bromo-4′-nitroacetophenone (0.155 mmol; 38 mg; AldrichChemical Co.) was added and the solution was allowed to reflux for 2.5h. The solution was allowed to cool and a solid was filtered and washedwith methanol and dried in vacuo. The crude product was dissolved inCH₂Cl₂ and 0.141 mmol of N-(2-mercapto)aminoethyl polystyrene resin(Calbiochem, San Diego, Calif.; 1.28 mmol/g; 110 mg) was added andallowed to stir overnight. The solution was filtered, concentrated anddried to afford 60 mg (90% yield) of crude methyl5-methylthio-4-[4-(4-nitrophenyl)(1,3-thiazol-2-yl)]thiophene-2-carboxylate.

b)5-Methylthio-4-[4-(4-nitrophenyl)(1,3-thiazol-2-yl)]thiophene-2-carboxamidinehydrochloride: To a stirred suspension of 1.66 mmol (90 mg) of ammoniumchloride (Fisher Scientific) in 2 mL of anhydrous toluene (AldrichChemical Co.) placed under nitrogen atmosphere at 0° C., 830 μL (1.66mmol) of 2M trimethylaluminum in toluene (Aldrich Chemical Co.) wasadded via syringe over 10 min and then let stir at 0° C. for 30 minafter which 60 mg (0.166 mmol) of5-methylthio-4-[4-(4-nitrophenyl)(1,3-thiazol-2-yl)]thiophene-2-carboxylatewas added to solution and allowed to reflux for 2.5 h. The reactionmixture was quenched by pouring over a slurry of 500 mg of silica in 10mL of chloroform. The silica was poured onto a sintered-glass funnel andwashed with a 10% methanol/CH₂Cl₂ solution and concentrated. The crudeproduct was purified on a 1 mm silica prep plate eluting with 10%methanol/CH₂Cl₂ to afford 12 mg (19% yield) of5-methylthio-4-[4-(4-nitrophenyl)(1,3-thiazol-2-yl)]thiophene-2-carboxamidinehydrochloride. ¹H-NMR (CD₃OD₃, 300 MHz) δ 8.58 (s, 1H), 8.32-8.33 (m,4H), 8.24 (s, 1H), 2.83 (s, 3H). Mass Spectrum (MALDI-TOF, CHCA matrix,m/z) Calcd. for C₁₅H₁₂N₄O₂S₃: 376.5(M+H), found 377.3.

EXAMPLE 124-[4-(3,4-Ethylenedioxyphenyl)thiazol-2-yl]-5-methylthiothiophene-2-carboxamidineHydrochloride

a) Methyl4-(4-(2H,3H-benzo[3,4-e]1,4-dioxin-6-yl)(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxylate:40 mg (0.162 mmol) of methyl4-(aminothioxomethyl)-5-methylthiothiophene-2-carboxylate (MaybridgeChemical Co. LTD., Cornwall, U.K.) was dissolved in 2 mL of reagentgrade acetone. 1-(2H,3H-benzo[e]1,4-dioxin-6-yl)-2-bromoethan-1-one(0.162 mmol; 42 mg; Maybridge Chemical Co. LTD., Cornwall, U.K.) wasadded and the solution was allowed to reflux for 3 h. The solution wasallowed to cool and allowed to stir for 2 days after which the reactionsolution was concentrated in vacuo. The crude product was dissolved in50 mL of CH₂Cl₂ and partitioned between 50 mL of 1N NaOH (aq.). Theorganic layer was obtained and dried over sodium sulfate andconcentrated to afford 60 mg (90% yield) of methyl4-[4-(3,4-ethylenedioxyphenyl)thiazol-2-yl]-5-methylthiothiophene-2-carboxylate.

b)4-[4-(3,4-Ethylenedioxyphenyl)thiazol-2-yl]-5-methylthiothiophene-2-carboxamidinehydrochloride: To a stirred suspension of 1.62 mmol (86 mg) of ammoniumchloride (Fisher Scientific) in 2 mL of anhydrous toluene (AldrichChemical Co.) placed under nitrogen atmosphere at 0° C., 810 μL (1.62mmol) of 2M trimethylaluminum in toluene (Aldrich Chemical Co.) wasadded via syringe over 10 min and then let stir at 0° C. for 30 minafter which 60 mg (0.162 mmol) of methyl4-[4-(3,4-ethylenedioxyphenyl)thiazol-2-yl]-5-methylthiothiophene-2-carboxylatewas added to solution and allowed to reflux for 2.5 h. The reactionmixture was quenched by pouring over a slurry of 500 mg of silica in 10mL of chloroform. The silica was poured onto a sintered glass funnel andwashed with a 10% methanol/CH₂Cl₂ solution and concentrated. The crudeproduct was purified on a 1 mm silica prep plate eluting with 10%methanol/CH₂Cl₂ to afford 47 mg (75% yield) of4-[4-(3,4-ethylenedioxyphenyl)thiazol-2-yl]-5-methylthiothiophene-2-carboxamidinehydrochloride. ¹H-NMR (CD₃OD; 300 MHz) δ 8.53 (s, 1H), 7.73 (s, 1H),7.56 (d, J=2 Hz, 1H), 7.50 (dd, J=2.1 Hz and 8.4 Hz, 1H), 6.89 (d, J=8.4Hz, 1H), 4.28 (s, 4H), 2.8 (s, 3H). Mass Spectrum (MALDI-TOF, CHCAmatrix, m/z) Calcd. for C₁₇H₁₅N₃O₂S₃: 389.5(M+H), found 390.1.

EXAMPLE 134-[4-(4-Methoxyphenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxamidineHydrochloride

a) Methyl4-]4-(4-methoxyphenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxylate:30 mg (0.122 mmol) of methyl4-(aminothioxomethyl)-5-methylthiothiophene-2-carboxylate (MaybridgeChemical Co. LTD., Cornwall, U.K.) was dissolved in 1.2 mL of reagentgrade acetone. 2-bromo-4′-methoxy acetophenone (0.146 mmol; 28 mg;Aldrich Chemical Co.) was added and the solution was allowed to refluxfor 3 h. The solution was allowed to cool and a solid was filtered andwashed with methanol and dried in vacuo to afford 46 mg (90% yield) ofmethyl4-[4-(4-methoxyphenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxylate.

b)4-[4-(4-Methoxyphenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxamidinehydrochloride: To a stirred suspension of 1.22 mmol (66 mg) of ammoniumchloride (Fisher Scientific) in 2 mL of anhydrous toluene (AldrichChemical Co.) placed under nitrogen atmosphere at 0° C., 612 μL (1.22mmol) of 2M trimethylaluminum in toluene (Aldrich Chemical Co.) wasadded via syringe over 10 min and then let stir at 0° C. for 30 minafter which 46 mg (0.122 mmol) of4-[4-(4-methoxyphenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxylatewas added to solution and allowed to reflux for 2.5 h. The reactionmixture was quenched by pouring over a slurry of 500 mg of silica in 10mL of chloroform. The silica was poured onto a sintered glass funnel andwashed with a 10% methanol/CH₂Cl₂ solution and concentrated. The crudeproduct was purified on a 1 mm silica prep plate eluting with 10%methanol/CH₂Cl₂ to afford 32 mg (73% yield) of4-[4-(4-methoxyphenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxamidinehydrochloride. ¹H-NMR (CD₃OD; 300 MHz) δ 8.53 (s, 1H), 7.98 (d, J=7 Hz,2H), 7.75 (s, 1H), 7.01 (d, J=5 Hz, 2H), 3.9 (s, 3H), 2.8 (s, 3H). MassSpectrum (MALDI-TOF, CHCA matrix, m/z) Calcd. for C₁₆H₁₅N₃OS₃: 362.0(M+H), found 362.2.

EXAMPLE 144-[4-(3,4-Propylenedioxyphenyl)thiazol-2-yl]-5-methylthiothiophene-2-carboxamidineHydrochloride

a) Methyl4-[4-(3,4-propylenedioxyphenyl)thiazol-2-yl]-5-methylthiothiophene-2-carboxylate:42 mg (0.170 mmol) of methyl4-(aminothioxomethyl)-5-methylthiothiophene-2-carboxylate (MaybridgeChemical Co. LTD., Cornwall, U.K.) was dissolved in 5 mL of reagentgrade acetone. 3′,4′-Propylenedioxy-2-bromoacetophenone (0.170 mmol; 28mg; Maybridge Chemical Co. LTD., Cornwall, U.K.) was added and thesolution was allowed to reflux for 3 h. The solution was allowed to cooland a solid was filtered and purified on a 1 mm silica prep plateeluting with 20% ethyl acetate/hexane and dried in vacuo to afford 42 mg(59% yield) of methyl4-[4-(3,4-propylenedioxyphenyl)thiazol-2-yl]-5-methylthiothiophene-2-carboxylate.

b)4-[4-(3,4-Propylenedioxyphenyl)thiazol-2-yl]-5-methylthiothiophene-2-carboxamidinehydrochloride: To a stirred suspension of 1.01 mmol (54 mg) of ammoniumchloride (Fisher Scientific) in 2 mL of anhydrous toluene (AldrichChemical Co.) placed under nitrogen atmosphere at 0° C., 510 μL (1.01mmol) of 2M trimethylaluminum in toluene (Aldrich Chemical Co.) wasadded via syringe over 10 min and then let stir at 0° C. for 30 minafter which 42 mg (0.101 mmol) of methyl4-[4-(3,4-propylenedioxyphenyl)thiazol-2-yl]-5-methylthiothiophene-2-carboxylatewas added to solution and allowed to reflux for 3 h. The reactionmixture was quenched by pouring over a slurry of 500 mg of silica in 20mL of chloroform. The silica was poured onto a sintered glass funnel andwashed with a 10% methanol/CH₂Cl₂ solution and concentrated to afford 20mg (50% yield) of4-[4-(3,4-propylenedioxyphenyl)thiazol-2-yl]-5-methylthiothiophene-2-carboxamidinehydrochloride. ¹H-NMR (CD₃OD; 300 MHz) δ 8.53 (s, 1H), 7.78 (s, 1H),7.68 (d, J=2.2 Hz, 1H), 7.60 (dd, J=2.2 Hz and 8.4 Hz, 1H), 7.00 (d,J=8.3 Hz; 1H), 4.19-4.28 (m, 4H), 2.77 (s, 3H), 2.18-2.23 (m, 2H). MassSpectrum (MALDI-TOF, CHCA matrix, m/z) Calcd. for C₁₈H₁₇N₃O₂S₃: 404.1(M+H), found 404.1.

EXAMPLE 155-Methylthio-4-(4-(2-thienyl)(1,3-thiazol-2-yl))thiophene-2-carboxamidineAcetate

a) 2-Bromo-1-(2-thienyl)ethan-1-one: To a solution of 500 mg (3.96 mmol)of 2-acetyl thiophene (Aldrich Chemical Co.) dissolved in 20 mL ofCHCl₃, was added 1 drop of 30% HBr/CH₃COOH (Aldrich Chemical Co.)followed by 3.96 mmol (633 mg; 204 μL) of bromine (Aldrich Chemical Co.)added dropwise over 30 min. The reaction was allowed to stir for 1 h.The solution was concentrated to an oil and dried in vacuo. The crudeproduct was purified on 1 mm silica prep plates eluting with neat CH₂Cl₂to obtain 300 mg (37% yield) of 2-bromo-1-(2-thienyl)ethan-1-one. ¹H-NMR(CDCl₃; 300 MHz) δ 7.80 (m, 2H), 7.18 (m, 1H), 4.37 (s, 2H).

b) Methyl5-methylthio-4-(4-(2-thienyl)(1,3-thiazol-2-yl))thiophene-2-carboxylate:44 mg (0.176 mmol) of methyl4-(aminothioxomethyl)-5-methylthiothiophene-2-carboxylate (MaybridgeChemical Co. LTD., Cornwall, U.K.) was dissolved in 3 mL of reagentgrade acetone. 2-Bromo-1-(2-thienyl)ethan-1-one (0.176 mmol; 36 mg) wasadded and the solution was allowed to reflux for 3 h. The solution wasallowed to cool and was concentrated. The crude product was dissolved in20 mL of CH₂Cl₂ and washed with 20 mL of 1N HCl (aq.). The organic layerwas obtained and dried over sodium sulfate to afford 115 mg (80% yield)of crude methyl5-methylthio-4-(4-(2-thienyl)(1,3-thiazol-2-yl))thiophene-2-carboxylate.

c)5-Methylthio-4-(4-(2-thienyl)(1,3-thiazol-2-yl))thiophene-2-carboxamidineacetate: To a stirred suspension of 2.80 mmol (150 mg) of ammoniumchloride (Fisher Scientific) in 5 mL of anhydrous toluene (AldrichChemical Co.) placed under nitrogen atmosphere at 0° C., 1.5 mL (2.8mmol) was added 2M trimethylaluminum in toluene (Aldrich Chemical Co.)via syringe over 15 min and then let stir at 0° C. for 25 min. afterwhich 115 mg (0.280 mmol) of methyl5-methylthio-4-(4-(2-thienyl)(1,3-thiazol-2-yl))thiophene-2-carboxylatein 5 mL of anhydrous toluene was added to solution and allowed to refluxfor 1.5 h. The reaction mixture was quenched by pouring over a slurry ofsilica in CH₂Cl₂. The silica was poured onto a sintered glass funnel andwashed with a 10% methanol/CH₂Cl₂ solution and concentrated. The crudeproduct was purified on a 1 mm silica prep plate eluting with 10%methanol/CH₂Cl₂ with 1% CH₃COOH to afford 40 mg (43% yield) of5-methylthio-4-(4-(2-thienyl)(1,3-thiazol-2-yl))thiophene-2-carboxamidineacetate. ¹H-NMR (CD₃OD; 300 MHz) δ 8.52 (s, 1H), 7.74 (s, 1H), 7.59 (dd,J=2 Hz and 5 Hz, 1H), 7.42 (dd, J=2 Hz and 5 Hz, 1H), 7.11 (m, 1H), 2.79(s, 3H). Mass Spectrum (MALDI-TOF, CHCA matrix, m/z) Calcd. forC₁₃H₁₁N₃S₄: 338.0 (M+H), found 337.9.

EXAMPLE 164-[4-(3-Bromophenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxamidineHydrochloride

a) Methyl4-[4-(3-bromophenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxylate:99 mg (0.400 mmol) of methyl4-(aminothioxomethyl)-5-methylthiothiophene-2-carboxylate (MaybridgeChemical Co. LTD., Cornwall, U.K.) was dissolved in 25 mL of reagentgrade acetone. 2-Bromo-3′-bromo acetophenone (0.4 mmol; 111 mg) wasadded and the solution was allowed to reflux for 3 h. The solution wasallowed to cool and a solid was filtered and dissolved in 5 mL of hottetrahydrofuran (THF), (Aldrich Chemical Co.) and purified on a 1 mmsilica prep plate eluting with 20% ethyl acetate/hexane and dried invacuo to afford 66 mg (40% yield) of methyl4-[4-(3-bromophenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxylate.

b)4-[4-(3-Bromophenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxamidinehydrochloride: To a stirred suspension of 1.55 mmol (83 mg) of ammoniumchloride (Fisher Scientific) in 10 mL of anhydrous toluene (AldrichChemical Co.) placed under nitrogen atmosphere at 0° C., 774 μL (1.55mmol) of 2M trimethylaluminum in toluene (Aldrich Chemical Co.) wasadded via syringe over 10 min and then let stir at 25° C. for 20 minafter which 66 mg (0.155 mmol) of4-[4-(3-bromophenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxylatewas added to solution and allowed to reflux for 3 h. The reactionmixture was quenched by pouring over a slurry of 5 g of silica in 25 mLof chloroform. The silica was poured onto a sintered glass funnel andwashed with a 10% methanol/CH₂Cl₂ solution and concentrated. The crudeproduct was purified on 1 mm silica plates eluting with 10%methanol/CH₂Cl₂ to afford 63 mg (90% yield) of4-[4-(3-bromophenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxamidinehydrochloride. ¹H-NMR (CD₃OD; 300 MHz) δ 8.49 (s, 1H), 8.21 (m, 1H),7.96 (m, 2H), 7.50 (m, 1H), 7.5 (m, 1H), 7.34 (m, 1H), 2.8 (s, 3H). MassSpectrum (MALDI-TOF, CHCA matrix, m/z) Calcd. for C₁₅H₁₂BrN₃S₃: 411.9(M+H), found 411.9.

EXAMPLE 174-[4-(4-Chloro-3-nitrophenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxamidineHydrochloride

a) Methyl4-[4-(4-chloro-3-nitrophenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxylate:50 mg (0.202 mmol) of methyl4-(aminothioxomethyl)-5-methylthiothiophene-2-carboxylate (MaybridgeChemical Co. LTD., Cornwall, U.K.) was dissolved in 10 mL of reagentgrade acetone. 2-Bromo-4′-chloro-3′-nitroacetophenone (0.212 mmol; 59mg) was added and the solution was allowed to reflux for 3 h. Thesolution was allowed to cool and a solid was filtered and dissolved inhot tetrahydrofuran (THF) and purified on a 1 mm silica prep plateeluting with 20% ethyl acetate/hexane and dried in vacuo to afford 60 mg(70% yield) of methyl4-[4-(4-chloro-3-nitrophenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxylate.

b)4-[4-(4-Chloro-3-nitrophenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxamidinehydrochloride: To a stirred suspension of 1.40 mmol (75 mg) of ammoniumchloride (Fisher Scientific) in 10 mL of anhydrous toluene (AldrichChemical Co.) placed under nitrogen atmosphere at 0° C., 700 μL (1.40mmol) of 2M trimethylaluminum in toluene (Aldrich Chemical Co.) wasadded via syringe over 10 min and then let stir for 20 min after which60 mg (0.140 mmol) of4-[4-(4-chloro-3-nitrophenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxylatewas added to solution and allowed to reflux for 3 h. The reactionmixture was quenched by pouring over a slurry of 5 g of silica in 50 mLof chloroform. The silica was poured onto a sintered glass funnel andwashed with a 10% methanol/CH₂Cl₂ solution and concentrated. The crudeproduct was purified on 1 mm silica plates eluting with 10%methanol/CH₂Cl₂ to afford 17 mg (32% yield) of4-[4-(4-chloro-3-nitrophenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxamidinehydrochloride. ¹H-NMR (CD₃OD; 300 MHz) δ 8.53-8.58 (m, 2H), 8.26 (dd,J=2.2 Hz and 8.5 Hz, 1H), 8.16 (s, 1H), 7.72 (d, J=8.5 Hz, 1H, 2.80 (s,3H).

EXAMPLE 184-[4-(4-Chloro-3-methylphenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxamidinehydrochloride

a) Methyl4-[4-(4-Chloro-3-methylphenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxylate:155 mg (0.627 mmol) of methyl4-(aminothioxomethyl)-5-methylthiothiophene-2-carboxylate (MaybridgeChemical Co. LTD., Cornwall, U.K.) was dissolved in 10 mL of reagentgrade acetone. 2-Bromo-1-(4-chloro-3-methylphenyl)ethan-1-one (0.658mmol; 163 mg) was added and the solution was allowed to reflux for 3 h.The solution was allowed to cool and the reaction mixture wasconcentrated and dissolved in 50 mL of CH₂Cl₂. The organic layer waswashed with 50 mL of 1N HCl (aq.), dried over sodium sulfate andconcentrated. The crude product was purified on a 1 mm silica plateeluting with 20% ethyl acetate/hexane to afford 168 mg (68% yield) ofmethyl4-[4-(4-chloro-3-methylphenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxylate.

b)4-[4-(4-Chloro-3-methylphenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxamidineHydrochloride: To a stirred suspension of 4.24 mmol (227 mg) of ammoniumchloride (Fisher Scientific) in 15 mL of anhydrous toluene (AldrichChemical Co.) placed under nitrogen atmosphere at 0° C., 2.2 mL (4.24mmol) of 2M trimethylaluminum in toluene (Aldrich Chemical Co.) wasadded via syringe over 10 min and then let stir for 20 min at 25° C.after which 168 mg (0.424 mmol) of methyl4-[4-(4-chloro-3-methylphenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxylatewas added to solution and allowed to reflux for 2.5 h. The reactionmixture was quenched by pouring over a slurry of 5 g silica inchloroform. The silica was poured onto a sintered glass funnel andwashed with a 10% methanol/CH₂Cl₂ solution and concentrated to afford117 mg (73% yield) of4-[4-(4-chloro-3-methylphenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxamidinehydrochloride. ¹H-NMR (CD₃OD; 300 MHz) δ 8.53 (s, 1H) 8.03 (dd, J=1.2 Hzand 2.7 Hz, 1H, 7.9 (s, 1H, 7.85 (dd, J=2 Hz and 8.5 Hz 1H, 7.38 (dd,J=8.3 Hz and 17.4 Hz, 1H, 2.8 (s, 3H) 2.45 (s, 3H). Mass Spectrum(MALDI-TOF, CHCA matrix, m/z) Calcd. for C₁₆H₁₄ClN₃S₃: 380.0 (M+H),found 380.3.

EXAMPLE 194-(5-Methyl-4-phenyl(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxamidineHydrochloride

a) Methyl4-(5-methyl-4-phenyl(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxylate:48 mg (0.194 mmol) of methyl4-(aminothioxomethyl)-5-methylthiothiophene-2-carboxylate (MaybridgeChemical Co. LTD., Cornwall, U.K.) was dissolved in 5 mL of reagentgrade acetone. 2-Bromo-1-phenylpropan-1-one (0.223 mmol; 48 mg) wasadded and the solution was allowed to reflux for 5 h. The solution wasallowed to cool and the reaction mixture was concentrated and dissolvedin 50 mL of CH₂Cl₂. The organic layer was washed with 50 mL of 1N HCl(aq.), dried over sodium sulfate and concentrated. The crude product waspurified on a 1 mm silica plate eluting with 20% ethyl acetate/hexane toafford 53 mg (76% yield) of methyl4-(5-methyl-4-phenyl(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxylate.

b)4-(5-Methyl-4-phenyl(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxamidinehydrochloride: To a stirred suspension of 1.47 mmol (78 mg) of ammoniumchloride (Fisher Scientific) in 5 mL of anhydrous toluene (AldrichChemical Co.) placed under nitrogen atmosphere at 0° C., 735 μL (1.47mmol) of 2M trimethylaluminum in toluene (Aldrich Chemical Co.) wasadded via syringe over 10 min and then let stir for 20 min at 25° C.then, 53 mg (0.147 mmol) of methyl4-(5-methyl-4-phenyl(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxylatewere added to solution and allowed to reflux for 2.5 h. The reactionmixture was quenched by pouring over a slurry of 5 g silica inchloroform. The silica was poured onto a sintered glass funnel andwashed with a 10% methanol/CH₂Cl₂ solution and concentrated to afford 26mg (51% yield) of4-(5-methyl-4-phenyl(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxamidinehydrochloride. ^(1H)-NMR (CD₃OD; 300 MHz) δ 8.45 (s, 1H, 7.74-7.77 (m,2H), 7.44-7.50 (m, 2H), 7.38-7.41 (m, 1H), 2.8 (s, 3H) 2.6 (s, 3H). MassSpectrum (MALDI-TOF, CHCA matrix, m/z) Calcd. for C₁₆H₁₅N₃S₃: 346.0(M+H), found 345.6.

EXAMPLE 204-[4-(4-Methylphenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxamidineTrifluoroacetate

a) Methyl4-[4-(4-methylphenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxylate:103 mg (0.416 mmol) of methyl4-(aminothioxomethyl)-5-methylthiothiophene-2-carboxylate (MaybridgeChemical Co. LTD., Cornwall, U.K.) was dissolved in 5 mL of reagentgrade acetone. 2-Bromo-4′-methyl acetophenone (0.416 mmol; 89 mg) wasadded and the solution was allowed to reflux for 3 h. The solution wasallowed to cool and crude product was filtered and washed two times withacetone and purified on a 1 mm silica plate eluting with 20% ethylacetate/hexane to afford 104 mg (69% yield) of methyl4-[4-(4-methylphenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxylate.

b)4-[4-(4-Methylphenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxamidinetrifluoroacetate: To a stirred suspension of 2.87 mmol (154 mg) ofammonium chloride (Fisher Scientific) in 10 mL of anhydrous toluene(Aldrich Chemical Co.) placed under nitrogen atmosphere at 0° C., 144 μL(2.87 mmol) of 2M trimethylaluminum in toluene (Aldrich Chemical Co.)was added via syringe over 10 min and then let stirred for 20 min at 25°C. after which 104 mg (0.287 mmol) of4-[4-(4-methylphenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxylatewas added to solution and allowed to reflux for 3 h. The reactionmixture was quenched by pouring over a slurry of 5 g of silica in 50 mLof chloroform. The silica was poured onto a sintered glass funnel andwashed with a 10% methanol/CH₂Cl₂ solution and concentrated. The crudeproduct was then purified on a 1 mm silica prep plate eluting with 10%methanol/CH₂Cl₂ with 1% CH₃COOH. The product was then basified with aq.NaOH and extracted with CHCl₃ and concentrated. TFA was added and theproduct was crystallized from methanol as4-[4-(4-methylphenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxamidinetrifluoroacetate (20 mg; 30% yield). ¹H-NMR (DMSO-d₆; 300 MHz) δ 8.62(s, 1H), 8.12 (s, 1H, 7.98 (d, 1H, J=8.1 Hz) 7.31 (d, 1H, J=8.1 Hz), 2.8(s, 3H) 2.5 (s, 3H). Mass Spectrum (MALDI-TOF, CHCA Matrix, m/z) Calcd.for C₁₆H₁₅N₃S₃: 346.0 (M+H), found 346.1.

EXAMPLE 214-[4-(2-methoxyphenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxamidineHydrochloride

a) Methyl4-[4-(2-Methoxyphenyl)(1,3-thiazol-2-yl)]-5-metmylthiothiophene-2-carboxylate:105 mg (0.424 mmol) of methyl4-(aminothioxomethyl)-5-methylthiothiophene-2-carboxylate (MaybridgeChemical Co. LTD., Cornwall, U.K.) was dissolved in 5 mL of reagentgrade acetone. 2-Bromo-2′-methoxy acetophenone (0.467 mmol; 110 mg) wasadded and the solution was allowed to reflux for 3 h. The solution wasallowed to cool and the solution concentrated. The crude product wasdissolved in 100 mL of CH₂Cl₂ and washed one time with 50 mL of 1N NaOH.The organic layer was obtained, dried over sodium sulfate, concentratedand purified on a 1 mm silica plate eluting with 20% ethylacetate/hexane to afford 160 mg (95% yield) of methyl4-[4-(2-methoxyphenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxylate.

b)4-[4-(2-Methoxyphenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxamidinehydrochloride: To a stirred suspension of 4.23 mmol (227 mg) of ammoniumchloride (Fisher Scientific) in 10 mL of anhydrous toluene placed undernitrogen atmosphere at 0° C., 2.12 mL (4.23 mmol) of 2Mtrimethylaluminum in toluene (Aldrich Chemical Co.) was added viasyringe over 10 min and then let stir for 20 min at 25° C. after which160 mg (0.287 mmol) of methyl4-[4-(2-methoxyphenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxylatein a solution of 5 mL of anhydrous toluene was added to solution andallowed to reflux for 3 h. The reaction mixture was quenched by pouringover a slurry of 5 g of silica in 30 mL of chloroform. The silica waspoured onto a sintered glass funnel and washed with a 10%methanol/CH₂Cl₂ solution and concentrated. The crude product was thenpurified on a 2 mm silica prep plate eluting with 10% methanol/CH₂Cl₂with 1% NH₄OH. The product was then dissolved in 2 mL of 4N HCl/dioxaneand concentrated to afford 45 mg (29% yield) of4-[4-(2-methoxyphenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxamidinehydrochloride. ¹H-NMR (DMSO-d₆; 300 MHz) δ 8.68 (s, 1H), 8.36 (dd, J=1.6Hz and 7.74 Hz, 1H), 8.21 (s, 1H), 7.36-7.42 (m, 1H), 7.05-7.22 (m, 3H),3.97 (s, 3H), 2.8 (s, 3H).

Mass Spectrum (MALDI-TOF, CHCA Matrix, m/z) Calcd. for C₁₆H₁₅N₃OS₃:362.0 (M+H), found 361.7.

EXAMPLE 224-[4-(2,4-Dimethoxyphenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxamidineHydrochloride

a) Methyl4-[4-(2,4dDimethoxyphenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxylate:99 mg (0.424 mmol) of methyl4-(aminothioxomethyl)-5-methylthiothiophene-2-carboxylate (MaybridgeChemical Co. LTD., Cornwall, U.K.) was dissolved in 5 mL of reagentgrade acetone. 2-Bromo-2′,4′-dimethoxyacetophenone (0.440 mmol; 114 mg)was added and the solution was allowed to reflux for 2.5 h. The solutionwas allowed to cool and the crude product was collected as a solid andwashed with methanol and dried yielding 91 mg (56% yield) of methyl4-[4-(2,4-dimethoxyphenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxylate.

b)4-[4-(2,4-Dimethoxyphenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxamidinehydrochloride: To a stirred suspension of 2.23 mmol (119 mg) of ammoniumchloride (Fisher Scientific) in 10 mL of anhydrous toluene placed undernitrogen atmosphere at 0° C., 1.1 mL (2.23 mmol) of 2M trimethylaluminumin toluene was added via syringe over 10 min and then let stirred for 20min at 25° C. after which 81 mg (0.223 mmol) of methyl4-[4-(2,4-dimethoxyphenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxylatewas added to solution and allowed to reflux for 2.5 h. The reactionmixture was quenched by pouring over a slurry of silica in chloroform.The silica was poured onto a sintered glass funnel and washed with a 10%methanol/CH₂Cl₂ solution and concentrated. The crude product was thenpurified on a 0.5 mm silica prep plate eluting with 10% methanol/CH₂Cl₂to afford 32 mg (37% yield) of4-[4-(2,4-dimethoxyphenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxamidinehydrochloride. ¹H-NMR (CD₃OD; 300 MHz) δ 8.49 (s, 1H), 8.31 (d, J=8.5Hz, 1H), 7.93 (s, 1H), 6.64 (m, 2H), 3.97 (s, 3H), 3.85 (s, 3H), 2.79(s, 3H). Mass Spectrum (MALDI-TOF, CHCA Matrix, m/z) Calcd. forC₁₇H₁₇N₃O₂S₃: 392.1 (M+H), found 392.4.

EXAMPLE 234-[4-(3,4-Dichlorophenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxamidineHydrochloride

a) Methyl4-[4-(3,4-dichlorophenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxylate:176 mg (0.712 mmol) of methyl4-(aminothioxomethyl)-5-methylthiothiophene-2-carboxylate (MaybridgeChemical Co. LTD., Cornwall, U.K.) was reacted with2-bromo-3′,4′-dichloroacetophenone (0.854 mmol; 330 mg) in a mannersimilar to Example 22, step (a) to afford 270 mg (91% yield) of methyl4-[4-(3,4-dichlorophenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxylate.

b)4-[4-(3,4-Dichlorophenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxamidinehydrochloride: 270 mg (0.648 mmol) of methyl4-[4-(3,4-dichlorophenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxylatewas treated in a manner similar to Example 22, step (b) to afford 135 mg(52% yield) of4-[4-(3,4-dichlorophenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxamidinehydrochloride. ¹H-NMR (CD₃OD; 300 MHz) δ 8.54 (s, 1H), 8.22 (d, J=2 Hz,1H), 8.02 (s, 1H), 7.94 (dd, J=2 Hz and 8.4 Hz, 1H), 7.58 (d, J=8.5 Hz,1H), 2.79 (s, 3H). Mass Spectrum (MALDI-TOF, CHCA Matrix, m/z) Calcd.for C₁₅H₁₁Cl₂N₃S₃: 400.0 (M+H), found 400.6.

EXAMPLE 244-[4-(3-Methylphenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxamidineHydrochloride

a) Methyl4-[4-(3-methylphenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxylate:Methyl 4-(aminothioxomethyl)-5-methylthiothiophene-2-carboxylate, 106 mg(0.428 mmol) (Maybridge Chemical Co. LTD., Cornwall, U.K.) was reactedwith 2-bromo-3′ methylacetophenone (0.428 mmol, 91 mg) in a mannersimilar to Example 22, step (a) to afford 98 mg (63% yield) of methyl4-[4-(3-methylphenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxylate.

b)4-[4-(3-Methylphenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxamidinehydrochloride:4-[4-(3-methylphenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxylate,(98 mg, 0.271 mmol) was treated in a similar manner to Example 22, step(b) to afford 75 mg (80% yield) of4-[4-(3-methylphenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxamidinehydrochloride. ¹H-NMR (CD₃OD; 300 MHz) δ 8.56 (s, 1H), 7.88 (s, 1H),7.86 (d, J=14 Hz, 2H), 7.33 (m, 1H), 7.19 (m, 1H), 2.79 (s, 3H), 2.42(s, 3H). Mass Spectrum (MALDI-TOF, CHCA Matrix, m/z) Calcd. forC₁₆H₁₅N₃S₃: 346.0 (M+H), found 346.7

EXAMPLE 255-Methylthio-4-(4-(2-5,6,7,8-tetrahydronaphthyl)(1,3-thiazol-2-yl))thiophene-2-carboxamidineHydrochloride

a) Methyl5-methylthio-4-(4-(2-5,6,7,8-tetrahydronaphthyl)(1,3-thiazol-2-yl))thiophene-2-carboxylate:Methyl 4-(aminothioxomethyl)-5-methylthiothiophene-2-carboxylate, (160mg, 0.647 mmol) (Maybridge Chemical Co. LTD., Cornwall, U.K.) wasreacted with 2-bromo-1-(2-5,6,7,8-tetrahydronaphthyl)ethan-1-one (0.712mmol; 180 mg) in a manner similar to Example 22, step (a) to afford 106mg (41% yield) of methyl5-methylthio-4-(4-(2-5,6,7,8-tetrahydronaphthyl)(1,3-thiazol-2-yl))thiophene-2-carboxylate.

b)5-Methylthio-4-(4-(2-5,6,7,8-tetrahydronaphthyl)(1,3-thiazol-2-yl))thiophene-2-carboxamidinehydrochloride: 106 mg (0.264 mmol) of methyl5-methylthio-4-(4-(2-5,6,7,8-tetrahydronaphthyl)(1,3-thiazol-2-yl))thiophene-2-carboxylatewas treated in a similar manner to Example 22, step (b) to afford 88 mg(80% yield) of5-methylthio-4-(4-(2-5,6,7,8-tetrahydronaphthyl)(1,3-thiazol-2-yl))thiophene-2-carboxamidinehydrochloride. ¹H-NMR (CD₃OD; 300 MHz) δ 8.49 (s, 1H), 7.78 (s, 1H),7.73 (m, 2H), 7.11 (m, 1H), 2.79 (m, 7H), 1.82-1.86 (m, 4H). MassSpectrum (MALDI-TOF, CHCA Matrix, m/z) Calcd. for C₁₉H₁₉N₃S₃: 386.1(M+H), found 386.2.

EXAMPLE 264-[4-(3,5-Dimethoxyphenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxamidineHydrochloride

a) Methyl4-[4-(3,5-dimethoxyphenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxylate:100 mg (0.404 mmol) of methyl4-(aminothioxomethyl)-5-methylthiothiophene-2-carboxylate (MaybridgeChemical Co. LTD., Cornwall, U.K.) was reacted with2-bromo-3′,5′-dimethoxy acetophenone (0.444 mmol) in a manner similar toExample 22, step (a) to afford 44 mg (27% yield) of methyl4-[4-(3,5-dimethoxyphenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxylate.

b)4-[4-(3,5-Dimethoxyphenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxamidinehydrochloride: 44 mg (0.108 mmol) of methyl4-[4-(3,5-dimethoxyphenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxylatewas treated in a manner similar to Example 22, step (b) to afford 25 mg(60% yield) of4-[4-(3,5-dimethoxyphenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxamidinehydrochloride. ¹H-NMR (CD₃OD; 300 MHz) δ 8.52 (s, 1H), 7.91 (s, 1H),7.23 (d, J=2.2 Hz, 1H), 6.50 (t, 1H), 3.85 (s, 6H), 2.89 (s, 3H). MassSpectrum (MALDI-TOF, CHCA Matrix, m/z) Calcd. for C₁₇H₁₇N₃O₂S₃: 392.11(M+H), found 392.4.

EXAMPLE 274-[4-(2-Methylphenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxamidineHydrochloride

a) Methyl4-[4-(2-methylphenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxylate:160 mg (0.647 mmol) of methyl4-(aminothioxomethyl)-5-methylthiothiophene-2-carboxylate (MaybridgeChemical Co. LTD., Cornwall, U.K.) was reacted with 2-bromo-2′-methylacetophenone (0.711 mmol. 152 mg) in a manner similar to Example 22,step (a) to afford 124 mg (53% yield) of methyl4-[4-(2-methylphenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxylate.

b)4-[4-(2-Methylphenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxamidinehydrochloride: 124 mg (0.343 mmol) of methyl4-[4-(2-methylphenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxylatewas treated in a manner similar to Example 22, step (b) to afford 60 mg(50% yield) of4-[4-(2-methylphenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxamidinehydrochloride. ¹H-NMR (CD₃OD; 300 MHz) δ 8.50 (s, 1H), 7.65 (m, 2H),7.22-7.32 (m, 3H), 2.79 (s, 3H), 2.51 (s, 3H). Mass Spectrum (MALDI-TOF,CHCA Matrix, m/z) Calcd. for C₁₆H₁₅N₃S₃: 346.0 (M+H), found 346.2.

EXAMPLE 284-[4-(2,5-Dimethoxyphenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxamidineHydrochloride

a) Methyl4-[4-(2,5-dimethoxyphenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxylate:132 mg (0.534 mmol) of methyl4-(aminothioxomethyl)-5-methylthiothiophene-2-carboxylate (MaybridgeChemical Co. LTD., Cornwall, U.K.) was reacted with2-bromo-2′,5′-dimethoxy acetophenone (0.587 mmol; 152 mg) in a mannersimilar to Example 22, step (a) to afford 97 mg (45% yield) of methyl4-[4-(2,5-dimethoxyphenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxylate.

b)4-[4-(2,5-Dimethoxyphenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxamidinehydrochloride: 97 mg (0.238 mmol) of methyl4-[4-(2,5-dimethoxyphenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxylatewas treated in a manner similar to Example 22, step (b) to afford 30 mg(32% yield) of4-[4-(2,5-dimethoxyphenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxamidinehydrochloride. ¹H-NMR (CD₃OD; 300 MHz) δ 8.46 (s, 1H), 8.10 (s, 1H),7.99 (d, J=3.2 Hz, 1H), 7.05 (d, J=9 Hz, 1H), 6.93 (d, J=3.2 Hz, 1H),6.90 (d, J=3.2 Hz, 1H), 3.94 (s, 3H), 3.83 (s, 3H), 2.51 (s, 3H). MassSpectrum (MALDI-TOF, CHCA Matrix, m/z) Calcd. for C₁₇H₁₇N₃O₂S₃: 392.1(M+H), found 392.1.

EXAMPLE 294-[4-(4-Chloro(3-pyridyl))(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxamidineHydrochloride

a) Methyl4-[4-(4-chloro(3-pyridyl))(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxylate:240 mg (0.970 mmol) of methyl4-(aminothioxomethyl)-5-methylthiothiophene-2-carboxylate (MaybridgeChemical Co. LTD., Cornwall, U.K.) was reacted with2-bromo-1-(4-chloro(3-pyridyl))ethan-1-one (1.06 mmol; 250 mg) in amanner similar to Example 22, step (a) to afford 286 mg (77% yield) ofmethyl4-[4-(4-chloro(3-pyridyl))(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxylate.

b)4-[4-(4-Chloro(3-pyridyl))(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxamidinehydrochloride: 286 mg (0.747 mmol) of methyl4-[4-(4-chloro(3-pyridyl))(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxylatewas treated in a manner similar to Example 22, step (b) to afford 134 mg(49% yield) of4-[4-(4-chloro(3-pyridyl))(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxamidinehydrochloride. Mass Spectrum (MALDI-TOF, CHCA Matrix, m/z) Calcd. forC₁₄H₁₁N₄ClS₃: 366.9 (M+H), found 366.6

EXAMPLE 304-(4-(2H-Benzo[d]1,3-dioxolen-5-yl)(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxamidineHydrochloride

a) 1-(2H-Benzo[3,4-d]1,3-dioxolen-5-yl)-2-bromoethan-1-one: To asolution of 2.5 g (15.23 mmol) of 3,4-methylenedioxy acetophenone in 200mL of anhydrous methanol was added 61 mmol (20 g) of poly(4-vinylpyridinium tribromide), Aldrich Chemical Co., and allowed toreflux for 2.5 h. The solution was filtered and concentrated.1-(2H-benzo[3,4-d]1,3-dioxolen-5-yl)-2-bromoethan-1-one (1.4 g, 38%yield) was obtained methylene chloride/hexanes as off-white crystals.¹H-NMR (DMSO-d₆; 300 MHz) δ 8.20 (s, 1H), 8.07 (s, 1H), 7.63 (m, 2H),7.03 (dd, J=1.2 Hz and 7.1 Hz, 1H), 6.09 (s, 2H), 3.86 (s, 3H), 2.75 (s,3H).

b) Methyl4-(4-(2H-benzo[d]1,3-dioxolen-5-yl)(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxylate:1.4 g (5.66 mmol) of methyl4-(aminothioxomethyl)-5-methylthiothiophene-2-carboxylate (MaybridgeChemical Co. LTD., Cornwall, U.K.) was reacted1-(2H-benzo[3,4-d]1,3-dioxolen-5-yl)-2-bromoethan-1-one (5.66 mmol, 1.37g) in a manner similar to Example 22, step (a) to afford 1.55 g (70%yield) of methyl4-(4-(2H-benzo[d]1,3-dioxolen-5-yl)(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxylate.

c)4-(4-(2H-Benzo[d],1,3-dioxolen-5-yl)(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxamidinehydrochloride: 1.55 g (3.95 mmol) of methyl4-(4-(2H-benzo[d]1,3-dioxolen-5-yl)(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxylatewas treated in a manner similar to Example 22, step (b) to afford 130 mg(9% yield) of4-(4-(2H-benzo[d]1,3-dioxolen-5-yl)(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxamidinehydrochloride. ¹H-NMR (CD₃OD; 300 MHz) δ 8.51 (s, 1H), 7.73 (s, 1H),7.58 (m, 2H), 6.89 (d, J=8 Hz, 1H), 6.00 (s, 2H), 2.79 (s, 3H). MassSpectrum (MALDI-TOF, CHCA Matrix. m/z) Calcd. for C₁₆H₁₃N₃O₂S₃: 376.0(M+H), found 376.1.

EXAMPLE 314-[4-(3,4-Dimethoxyphenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxamidineHydrochloride

a) 1-(3,4-Dimethoxyphenyl)-2-bromoethan-1-one: 2 g of1-(3,4-dimethoxyphenyl)ethan-1-one (11.1 mmol) was reacted in a mannersimilar to Example 15, step (a), to yield 1.2 g (42% yield) of1-(3,4-dimethoxyphenyl)-2-bromoethan-1-one.

b) Methyl4-[4-(3,4-dimethoxyphenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxylate:105 mg (0.424 mmol) of methyl4-(aminothioxomethyl)-5-methylthiothiophene-2-carboxylate (MaybridgeChemical Co. LTD., Cornwall, U.K.) was reacted with1-(3,4-dimethoxyphenyl)-2-bromoethan-1-one (0.467 mmol; 120 mg) in amanner similar to Example 22, step (a) to afford 148 mg (85% yield) ofmethyl4-[4-(3,4-dimethoxyphenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxylate.

c)4-[4-(3,4-Dimethoxyphenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxamidinehydrochloride: 148 mg (0.363 mmol) of methyl4-[4-(3,4-dimethoxyphenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxylatewas reacted in a manner similar to Example 22, step (b) to afford 70 mg(50% yield) of4-[4-(3,4-dimethoxyphenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxamidinehydrochloride. ¹H-NMR (CD₃OD; 300 MHz) δ 8.50 (s, 1H), 7.76 (s, 1H),7.61 (m, 23H), 7.31 (m, 1H), 7.01 (d, J=8 Hz, 1H), 3.9 (s, 3H) 3.86 (s,3H), 2.78 (s, 3H). Mass Spectrum (MALDI-TOF, CHCA Matrix, m/z) Calcd.for C₁₇H₁₇N₃O₂S₃: 392.1 (M+H), found 392.4.

EXAMPLE 324-[-(2-Chloro(3-pyridyl))(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxamidine

a) Methyl4-[4-(2-chloro(3-pyridyl))(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxylate:2-Chloropyridine-3-carbonyl chloride (300 mg, 1.7 mmol) was dissolved inanhydrous CH₃CN (4 mL). While stirring well with a magnetic stirrer,trimethylsilyldiazomethane (4 mL, 2M solution in hexane, 8 mmol) wasdripped into the reaction mixture. The resulting yellow solution wasstirred for 2 h at room temperature, at which time the mixture wascooled in an ice bath. To the cold solution, 30% HBr in acetic acid (2mL) was added dropwise with vigorous evolution of gas. This solution wasstirred for 1 h during which time2-bromo-1-(2-chloro(3-pyridyl))ethan-1-one precipitated. This solid wascollected by filtration and dried under vacuum. The dry solid (142 mg,0.6 mmol) was dissolved in acetone (10 ml). To this solution5-(methoxycarbonyl)-2-(methylthio)-thiophene-3-thiocarboxamide (100 mg,0.4 mmol, Maybridge Chemical Company, Cornwall, UK) was added and heatedat reflux for 5 h. At this point the solid that precipitated wasfiltered off and washed with methanol and dried under vacuum to give 110mg (71%) of methyl4-[4-(2-chloro(3-pyridyl))(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxylate.¹H-NMR (CDCl₃; 300 MHz) δ 2.70 (s, 3H), 3.92 (s, 3H), 7.39 (dd, J=4.7and 7.7 Hz, 1H), 8.11 (s, 1H), 8.22 (s, 1H), 8.38 (dd, J=1.9 and 4.7 Hz,1H), 8.62 (dd, J=1.9 and 7.7 Hz, 1H).

b)4-[4-(2-Chloro(3-pyridyl))(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxamidine:Methyl4-[4-(2-chloro(3-pyridyl))(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxylate(100 mg, 0.26 mmol) as prepared in previous step was treated in a mannersimilar to that for Example 1, to give 50 mg (52%) of4-[4-(2-chloro(3-pyridyl))(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxamidineas a solid. ¹H-NMR (DMSO-d₆; 300 MHz) δ 2.79 (s, 3H), 7.62 (dd, J=4.9and 7.4 Hz, 1H), 8.41 (s, 1H), 8.49 (m, 2H), 8.69 (s, 1H), 9.1 (broad s,2H), 9.4 (broad s, 2H). Mass spectrum (ESI, m/z): Calcd. forC₁₄H₁₁N₄S₃Cl: 367.0 (M+H), found 369.0.

EXAMPLE 334-(4-Cyclohexyl(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxamidine

a) Methyl4-(4-cyclohexyl(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxylate:Cyclohexanecarbonyl chloride (300 mg, 2.0 mmol) was treated in a mannersimilar to that for Example 32 to give 2-bromo-1-cyclohexylethan-1-one.The dry solid (125 mg) was dissolved in acetone (10 ml). To thissolution 5-(methoxycarbonyl)-2-(methylthio)-thiophene-3-thiocarboxamide(100 mg, 0.4 mmol, Maybridge Chemical Company, Cornwall, UK) was addedand heated at reflux for 5 h. At this point the solid that precipitatedwas filtered off and washed with methanol and dried under vacuum to give100 mg (70%) of methyl4-(4-cyclohexyl(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxylatewhich was used without further purification in the following step.

b)4-(4-Cyclohexyl(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxamidine:Methyl4-(4-cyclohexyl(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxylate(100 mg, 0.28 mmol) as prepared in previous step was treated in a mannersimilar to that for Example 1, to give 60 mg (63%) of4-(4-cyclohexyl(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxamidineas a solid. ¹H-NMR (DMSO-d₆; 300 MHz) δ 1.21-1.53 (m, 5H), 1.61-1.78 (m,3H), 2.05 (m, 2H), 2.7 (s, 3H), 2.74 (m, 1H), 7.33 (s, 1H), 8.32 (s,1H). Mass spectrum (MALDI-TOF, m/z): Calcd. for C₁₅H₁₉N₃S₃, 338.1 (M+H),found 338.1.

EXAMPLE 34 4-Phenyl-5-(trifluoromethyl)thiophene-2-carboxamidine

Methyl 4-phenyl-5-(trifluoromethyl)thiophene-2-carboxylate (100 mg, 0.37mmol, Maybridge Chemical Company, Cornwall, UK) was treated in a mannersimilar to that for Example 1 to give 80 mg (85%) of4-phenyl-5-(trifluoromethyl)thiophene-2-carboxamidine as a solid. ¹H-NMR(DMSO-d₆; 300 MHz) δ 7.45-7.52 (m, 5H), 7.79 (d, J=1.4 Hz, 1H). Massspectrum (MALDI-TOF, m/z): Calcd. for C₁₂H₉F₃N₂S, 271.1 (M+H), found271.2.

EXAMPLE 355-Methylthio-4-(2-phenyl(1,3-thiazol-4-yl))thiophene-2-carboxamidine

a) Methyl 4-(2-bromoacetyl)-5-methylthiothiophene-2-carboxylate:5-(Methoxycarbonyl)-2-methylthiothiophene-3-carboxylic acid (200 mg,0.86 mmol) as prepared in Example 95 was taken in a round bottomed flaskand anhydrous CH₂Cl₂ (10 mL) was introduced to the flask. This solutionwas cooled in an ice bath under an argon atmosphere. To this mixtureoxalyl chloride (328 mg, 2.6 mmol) was added followed by anhydrous DMF(500 μL). The resulting solution was stirred at 4° C. for 30 min andthen allowed to warm up to room temperature, while monitoring for thedisappearance of the acid by TLC. After 2 h solvents were removed undervacuum and the residual oxalyl chloride was removed azeotropically withtoluene. The resulting residue was dried under high-vacuum to give theacid chloride as a gray solid. This solid was dissolved in anhydrousCH₃CN (8 mL). While stirring well with a magnetic stirrertrimethylsilyldiazomethane (4 mL, 8 mmol, 2M solution in hexane) wasdripped into the reaction mixture. The resulting yellow solution wasstirred for 2 h at room temperature, at which time the mixture wascooled in an ice bath. To the cold solution 30% HBr in acetic acid (2mL) was added dropwise, with vigorous evolution of gas. This solutionwas stirred for 1 h, during which methyl4-(2-bromoacetyl)-5-methylthiothiophene-2-carboxylate precipitates. Thissolid was collected by filtration and dried under vacuum to give 120 mg(45%). ¹H-NMR (CDCl₃; 300 MHz) δ 2.64 (s, 3H), 3.91 (s, 3H), 4.27 (s,2H), 8.10 (s, 1H).

b) Methyl5-methylthio-4-(2-phenyl(1,3-thiazol-4-yl))thiophene-2-carboxylate:5-(Methoxycarbonyl)-2-(methylthio)-thiophene-3-thiocarboxamide (100 mg,0.4 mmol, Maybridge Chemical Company, Cornwall, UK) was dissolved inacetone (20 ml). To this solution, methyl4-(2-bromoacetyl)-5-methylthiothiophene-2-carboxylate (112 mg) asprepared in previous step was added and heated at reflux for 3 h. Atthis point the solid that precipitated was filtered off and washed withacetone and dried under vacuum to give 82 mg (65%) of methyl5-methylthio-4-(2-phenyl(1,3-thiazol-4-yl))thiophene-2-carboxylate.¹H-NMR (CDCl₃; 300 MHz) δ 2.67 (s, 3H), 3.91 (s, 3H), 7.44-7.49 (m, 3H),7.61 (s, 1H), 8.03-8.06 (m, 2H), 8.28 (s, 1H).

c) 5-Methylthio-4-(2-phenyl(1,3-thiazol-4-yl))thiophene-2-carboxamidine:Methyl5-methylthio-4-(2-phenyl(1,3-thiazol-4-yl))thiophene-2-carboxylate (80mg) as prepared in previous step was treated in a manner similar to thatfor Example 1, to give 50 mg of5-methylthio-4-(2-phenyl(1,3-thiazol-4-yl))thiophene-2-carboxamidine asa solid. ¹H-NMR (DMSO-d₆; 300 MHz) δ 2.75 (s, 3H), 7.51-7.60 (m, 3H),8.02 (s, 1H), 8.06 (m, 2H), 8.70 (s, 1H), 9.06 (broad s, 2H), 9.38(broad s, 2H). Mass spectrum (MALDI-TOF, m/z): Calcd. for C₁₅H₁₃N₃S₃,332.0 (M+H), found 332.1.

EXAMPLE 364-[4-(2-Chloro(4-pyridyl))(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxamidine

a) Methyl4-[4-(2-chloro(4-pyridyl))(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxylate:2-Chloropyridine-4-carbonyl chloride (300 mg, 1.7 mmol) was dissolved inanhydrous CH₃CN (4 mL). While stirring well with a magnetic stirrertrimethylsilyldiazomethane (4 mL, 8 mmol, 2M solution in hexane) wasdripped into the reaction mixture. The resulting yellow solution wasstirred for 2 h at room temperature, at which time the mixture wascooled in an ice bath. To the cold solution 30% HBr in acetic acid (2mL) was added dropwise, with vigorous evolution of gas. This solutionwas stirred for 1 h, during which time2-bromo-1-(2-chloro(4-pyridyl))ethan-1-one precipitates. This solid wascollected by filtration and dried under vacuum. The dry solid (142 mg,0.6 mmol) was dissolved in acetone (10 ml). To this solution5-(methoxycarbonyl)-2-(methylthio)-thiophene-3-thiocarboxamide (100 mg,0.4 mmol, Maybridge Chemical Company, Cornwall, UK) was added and heatedat reflux for 5 h. At this point the solid that precipitated wasfiltered off and washed with methanol and dried under vacuum to give 100mg of methyl4-[4-(2-chloro(4-pyridyl))(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxylate.¹H-NMR (CD₃OD; 300 MHz) δ 2.73 (s, 3H), 3.94 (s, 3H, overlapping H₂Opeak), 7.92-7.99 (m, 2H), 8.05 (s, 1H), 8.24 (s, 2H), 8.48 (m, 1H).

b)4-[4-(2-Chloro(4-pyridyl))(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxamidine:Methyl4-[4-(2-chloro(4-pyridyl))(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxylate(100 mg, 0.26 mmol) as prepared in previous step was treated in a mannersimilar to that for Example 1, to give 50 mg of4-[4-(2-chloro(4-pyridyl))(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxamidineas a solid. ¹H-NMR (CDCl₃/CD₃OD; 300 MHz) δ 2.82 (s, 3H), 7.95 (dd,J=1.4 and 5.3 Hz, 1H), 8.08 (d, J=1.0 Hz, 1H), 8.23 (s, 1H), 8.42 (d,J=5.3 Hz, 1H), 8.56 (s, 1H). Mass spectrum (MALDI-TOF, m/z): Calcd. forC₁₄H₁₁N₄S₃Cl, 367.0 (M+H), found 367.1.

EXAMPLE 374[-(4-Chlorophenyl)(1,3-thiazol-2-yl)]-5-(methylsulfonyl)thiophene-2-carboxamidine

4-[4-(4-Chlorophenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxamidine(35 mg, 0.1 mmol) prepared according to Example 1 was dissolved in amixture of MeOH and CH₂Cl₂ (1:1, 6 mL). While stirring well,m-chloroperoxybenzoic acid (100 mg) was added in portions to thissolution over a 3 h period. The mixture was stirred for a further 2 hand the solvents were removed under vacuum. The resulting residue wasdissolved in MeOH (8 mL). Strong anion exchange resin (AG 1-X8, 5 ml,1.4 meq/mL) was packed into a disposable chromatography column andwashed with H₂O (5×5 mL) and MeOH (3×5 mL). The methanolic solution fromthe reaction was slowly introduced into this column, and the columneffluent was collected. The column was washed with MeOH (2×5 mL) andthese washings were also collected. The combined effluents wereevaporated under vacuum and the residue was subjected to preparativethin layer chromatography (silica gel, 10% MeOH in CH₂Cl₂ with 2% aceticacid). The major band was isolated and suspended in CH₂Cl₂ and filtered.The filtrate was collected and the residue was washed with 10% MeOH inCH₂Cl₂ saturated with NH₃. The washings were combined with the originalfiltrate and the solvents were removed under vacuum. The resulting solidwas dissolved in 10% MeOH in CHCl₃ and filtered through a 0.45 micronfilter. The filtrate was collected and evaporated under vacuum to give20 mg (53%) of an off-white solid. ¹H-NMR (CDCl₃/CD₃OD; 300 MHz) δ 3.78(s, 3H), 7.47 (d, J=8.7 Hz, 2H), 7.96 (d, J=8.7 Hz, 1H), 8.00 (s, 1H),8.35 (s, 1H). Mass spectrum (MALDI-TOF, m/z): Calcd. for C₁₅H₁₂O₂N₃S₃Cl,398.0 (M+H), found 398.0.

EXAMPLE 38Hydrazino[5-methylthio-4-(4-phenyl(1,3-thiazol-2-yl))(2-thienyl)]methanimine

a) 5-Methylthio-4-(4-phenyl(1,3-thiazol-2-yl))thiophene-2-carboxamide:Liquid ammonia (5 mL) was condensed into a cold (−78° C). Teflon-linedsteel bomb. Methyl5-methylthio-4-(4-phenyl(1,3-thiazol-2-yl))thiophene-2-carboxylate (0.6g, 1.7 mmol) as prepared in Example 10 step (a) was introduced in oneportion and the bomb was sealed and heated in an oil bath at 80° C. for48 h. The bomb was cooled to −78° C., opened and the ammonia was allowedto evaporate at room temperature. The residual solid was collected anddried under vacuum to give 0.5 g (88%) of5-methylthio-4-(4-phenyl(1,3-thiazol-2-yl))thiophene-2-carboxamide.¹H-NMR (DMSO-d₆; 300 MHz) δ 2.75 (s, 3H), 7.38 (m, 1H), 7.40-7.51 (m,2H), 8.04-8.18 (m, 2H), 8.19 (s, 1H), 8.20 (s, 1H).

b) 5-Methylthio-4-(4-phenyl(1,3-thiazol-2-yl))thiophene-2-carbonitrile:A slurry of P₂O₅(2.7 g, 19 mmol) and hexamethyldisiloxane (6.7 mL) indichloroethane (13 ml,) was heated to 90° C., while stirring under a N₂atmosphere. After stirring for 2 h, the resulting clear solution wasallowed to cool to 40° C.5-methylthio-4-(4-phenyl(1,3-thiazol-2-yl))thiophene-2-carboxamide (0.9g, 2.7 mmol) as prepared in previous step was added to this solution andthe mixture was heated at 75° C. for 5 h. This solution was cooled toroom temperature and stirred with aqueous NaCl (6 M, 100 mL) for 10 min.As the aqueous solution is added a yellow solid precipitated. After 10min this solid was separated by filtration, and dried under vacuum togive (0.5 g, 59%) of5-methylthio-4-(4-phenyl(1,3-thiazol-2-yl))thiophene-2-carbonitrile as ayellow solid. ¹H-NMR(DMSO-d₆; 300 MHz) δ 2.76 (s, 3H), 7.38 (m, 1H),7.48 (m, 2H), 8.07 (m, 2H), 8.22 (s, 1H), 8.51 (s, 1H).

c)Hydrazino[5-methylthio-4-(4-phenyl(1,3-thiazol-2-yl))(2-thienyl)]methanimine:5-Methylthio-4-(4-phenyl(1,3-thiazol-2-yl))thiophene-2-carbonitrile (100mg, 0.32 mmol) as prepared in previous step was dissolved in EtOH (10mL). To this solution hydrazine monohydrate (10 eq) was added and themixture was heated at reflux for 3 h. The EtOH solution was concentrateddown to 1 mL and water (2 mL) was added to this solution. This resultedin the formation of a white solid. The solid was collected by filtrationwashed with a small amount of water and dried under vacuum to give 50 mg(45%) ofhydrazino[5-methylthio-4-(4-phenyl(1,3-thiazol-2-yl))(2-thienyl)]methanimine.¹H-NMR (CD₃OD/CDCl₃; 300 MHz) δ 2.69 (s, 3H), 7.39 (m, 1H), 7.47 (m,2H), 7.52 (s, 1H), 7.98 (m, 2H), 8.10 (s, 1H). Mass spectrum (ESI, m/z):Calcd. for C₁₅H₁₄N₄S₃, 347.04 (M+H), found 347.1.

EXAMPLE 39{Imino[5-methylthio-4-(4-phenyl(1,3-thiazol-2-yl))(2-thienyl)]methyl}methylamine

5-Methylthio-4-(4-phenyl(1,3-thiazol-2-yl))thiophene-2-carboxamidine (20mg, 0.06 mmol) as prepared in Example 10 step (b) was dissolved in MeOH,and to this solution methylamine (0.6 mL, 2M solution intetrahydrofuran) was added. This solution was refluxed for 6 h, at whichtime the solvents were removed under vacuum to give a solid. This solidwas dissolved in a small amount of MeOH. H₂O was added dropwise to themethanolic solution until a precipitate was formed. This solid wasisolated, washed with a small amount of water and dried under vacuum togive 15 mg (72%) of{imino[5-methylthio-4-(4-phenyl(1,3-thiazol-2-yl))(2-thienyl)]methyl}methylamine.¹H-NMR (DMSO-d₆; 300 MHz) δ 2.77 (s, 3H), 3.00 (s, 3H), 7.36-7.42 (m,1H), 7.47-7.52 (m, 2H), 8.07-8.10 (m, 2H), 8.23 (s, 1H), 8.55 (s, 1H).Mass spectrum (ESI, m/z): Calcd. for C₁₆H₁₅N₃S₃, 346.5 (M+H), found346.2.

EXAMPLE 402-{3-[2-(5-Amidino-2-methylthio-3-thienyl)-1,3-thiazol-4-yl]phenoxy}aceticAcid

a) 2-Bromo-1-(3-hydroxyphenyl)ethan-1-one:2-Bromo-1-(3-methoxyphenyl)ethan-1-one (2 g, 8.7 mmol) was taken in around bottomed flask equipped with magnetic stir bar. The flask was putunder a N₂ atmosphere and CH₂Cl₂ was introduced into the flask. Theresulting solution was cooled in a dry ice-acetone bath and BBr₃ (27 mL,1M in CH₂Cl₂) was introduced dropwise. The resulting solution wasallowed to warm up to room temperature overnight. The solvents wereremoved under vacuum and the residue was purified by passing through ashort pad of silica gel (50 g) to give 1.3 g (69%) of2-bromo-1-(3-hydroxyphenyl)ethan-1-one as an oil. ¹H-NMR (CDCl₃; 300MHz) δ 4.47 (s, 2H), 6.21 (s, 1H), 7.14 (m, 1H), 7.35 (m, 1H), 7.52-7.82(m, 2H).

b) Methyl4-[4-(3-hydroxyphenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxylate:2-Bromo-1-(3-hydroxyphenyl)ethan-1-one (229 mg, 1.1 mmol) as prepared inprevious step was treated in a manner similar to that of Example 13,step (a) to give 225 mg (61%) of methyl4-[4-(3-hydroxyphenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxylateas a solid. ¹H-NMR (DMSO-d₆; 300 MHz) δ 2.76 (s, 3H), 3.86 (s, 3H), 6.87(m, 1H), 7.27 (t, J=7.8 Hz, 1H), 7.49 (m, 2H), 8.12 (s, 1H), 8.20 (s,1H).

c)(tert-Butoxy)-N-({4-[4-(3-hydroxyphenyl)(1,3-thiazol-2-yl)]-5-methylthio(2-thienyl)}iminomethyl)carboxamide:4-[4-(3-Hydroxyphenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxamidine(2 g, 5.8 mmol), prepared by treating methyl4-[4-(3-hydroxyphenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxylatein a manner similar to that for Example 1, was dissolved in anhydrousDMF (10 mL). To this solution di-tert-butyl dicarbonate (1.38 g, 6.3mmol) and DIEA (2 mL, 11.5 mmol) was added, and the mixture was stirredat room temperature for 18 h. DMF was removed under vacuum and theresidue was purified by silica gel column chromatography to give 1.8 g(70%) of(tert-butoxy)-N-({4-[4-(3-hydroxyphenyl)(1,3-thiazol-2-yl)]-5-methylthio(2-thienyl)}iminomethyl)carboxamideas an oil. ¹H-NMR (DMSO-d₆; 300 MHz) δ 1.58 (s, 9H), 2.81 (s, 3H), 6.81(m, 1H), 7.28 (t, J=8.0 Hz, 1H), 7.49-7.52 (m, 2H), 8.09 (s, 1H), 8.71(s, 1H).

d) tert-Butyl2-{3-[2-(5-{[(tert-butoxy)carbonylamino]iminomethyl}-2-methylthio-3-thienyl)-1,3-thiazol-4-yl]phenoxy}acetate:(tert-Butoxy)-N-({4-[4-(3-hydroxyphenyl)(1,3-thiazol-2-yl)]-5-methylthio(2-thienyl)}iminomethyl)carboxamide(23 mg, 0.05 mmol) as prepared in previous step was dissolved inanhydrous DMF (1 mL). To this solution tert-butyl 2-bromoacetate (20 mg,0.1 mmol), Cs₂CO₃ (33.5 mg, 0.1 mmol) and KI (5 mg) was added and themixture was heated at 70° C. for 18 h. The solvents were removed undervacuum and the residue was purified by preparative silica gel thin-layerchromatography to give 12 mg (42%) of tert-butyl2-{3-[2-(5-{[(tert-butoxy)carbonylamino]iminomethyl}-2-methylthio-3-thienyl)-1,3-thiazol-4-yl]phenoxy}acetatewhich was used in the following step.

e)2-{3-[2-(5-Amidino-2-methylthio-3-thienyl)-1,3-thiazol-4-yl]phenoxy}aceticacid: tert-Butyl2-{3-[2-(5-{[(tert-butoxy)carbonylamino]iminomethyl}-2-methylthio-3-thienyl)-1,3-thiazol-4-yl]phenoxy}acetate(12 mg, 0.02 mmol) as prepared in previous step was dissolved in 1 ml50% TFA in CH₂Cl₂ containing 2% H₂O and stirred for 4 h. The solventswere removed under vacuum. The residual TFA was removed by azeotropingwith toluene to give 8.7 mg (100%) of2-{3-[2-(5-amidino-2-methylthio-3-thienyl)-1,3-thiazol-4-yl]phenoxy}aceticacid as a buff colored solid. ¹H-NMR (CD₃OD/CDCl₃; 300 MHz) δ 2.77 (s,3H), 4.74 (S, 2H), 6.93 (m, 1H), 7.35 (t, J=7.9 Hz, 1H), 7.62 (m, 1H),7.68 (M, 1H), 7.84 (s, 1H), 8.46 (s, 1H). Mass spectrum (ESI, m/z):Calcd. for C₁₇H₁₅N₃O₃S₃, 406.5 (M+H), found 406.3.

EXAMPLE 412-{2-[2-(5-Amidino-2-methylthio-3-thienyl)-1,3-thiazol-4-yl]phenoxy}aceticAcid

a) tert-Butyl2-{2-[2-(5-{[(tert-butoxy)carbonylamino]iminomethyl}-2-methylthio-3-thienyl)-1,3-thiazol-4-yl]phenoxy}acetate:4-[4-(2-Hydroxyphenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxamidine(100 mg, 0.29 mmol) as prepared in Example 196 step (b) was treated in amanner similar to that shown in Example 40 step (c) to give 100 mg (0.22mmol, 77%) of(tert-butoxy)-N-({4-[4-(2-hydroxyphenyl)(1,3-thiazol-2-yl)]-5-methylthio(2-thienyl)}iminomethyl)carboxamide.This compound was treated in a manner similar to that shown in Example40, step (d) to give 63 mg (50%) of tert-butyl2-{2-[2-(5-{[(tert-butoxy)carbonylamino]iminomethyl}-2-methylthio-3-thienyl)-1,3-thiazol-4-yl]phenoxy}acetate.¹H-NMR (CDCl₃; 300 MHz) δ 1.55 (s, 9H), 1.56 (s, 9H), 2.69 (s, 3H), 4.66(s, 2H), 6.88 (dd, J=0.8 and 8.3 Hz, 1H), 7.14 (dt, J=1.0 and 7.6 Hz,1H), 7.30 (m, 1H), 8.08 (s, 1H), 8.48 (dd, J=1.8 and 7.8 Hz, 1H), 8.51(s, 1H).

b)2-{2-[2-(5-Amidino-2-methylthio-3-thienyl)-1,3-thiazol-4-yl]phenoxy}aceticacid: tert-Butyl2-{2-[2-(5-{[(tert-butoxy)carbonylamino]iminomethyl}-2-methylthio-3-thienyl)-1,3-thiazol-4-yl]phenoxy}acetate(60 mg, 0.12 mmol) as prepared in previous step was treated in a mannersimilar to that shown in Example 40, step (e) to give 22 mg (50%) of2-{2-[2-(5-amidino-2-methylthio-3-thienyl)-1,3-thiazol-4-yl]phenoxy}aceticacid. ¹H-NMR (DMSO-d₆; 300 MHz) δ 2.80 (s, 3H), 4.90 (s, 2H), 7.17 (m,2H), 7.36 (m, 1H), 8.41 (d, J=6.3 Hz, 1H), 8.60 (s, 1H), 8.62 (s, 1H),9.00 (broad s, 2H), 9.37 (broad s, 2H). Mass spectrum (ESI, m/z): Calcd.for C₁₇H₁₅N₃O₃S₃, 406.5 (M+H), Found 406.1.

EXAMPLE 42 5-Methylthio-4-(6-phenyl(2-pyridyl))thiophene-2-carboxamidine

a) Methyl4-(1,1-dimethyl-1-stannaethyl)-5-methylthiothiophene-2-carboxylate:4-Bromo-5-methylthiothiophene-2-carboxylic acid (EP 0676395 A2) (4.67 g,18.4 mmol) was dissolved in anhydrous 1THF (30 mL), taken in a roundbottomed flask and cooled to −78° C. under a N₂ atmosphere. To thissolution n-butyllithium (20.3 mL, 40.6 mmol, 2M in cyclohexane) wasintroduced in a dropwise manner. The resulting solution was stirred at−78° C. for 45 min and then allowed to warm up to −60° C. To thissolution trimethyltin chloride (40.6 mL, 40.6 mmol, 1M in THF) was addeddropwise. This solution was stirred at −60° C. for 30 min and thenallowed to warm up to room temperature. The THF was removed under vacuumand the residue was treated with H₂O and extracted with hexane. Thehexane layer was evaporated and the residue was dissolved in Et₂O. TheEt₂O solution was washed with 10% HCl, saturated NaCl and dried overanhydrous MgSO₄. Et₂O was removed under vacuum and the residue was takenin MeOH. The MeOH solution was treated with trimethylsilyldiazomethane(18.5 mL, 2M in hexane) and stirred at room temperature for 1 h. Thesolvents were removed under vacuum to give 2 g (31%) of methyl4-(1,1-dimethyl-1-stannaethyl)-5-methylthiothiophene-2-carboxylate as anoil. ¹H-NMR (CDCl₃; 300 MHz) δ 0.31 (s, 9H), 2.57 (s, 3H), 3.86 (s, 3H),6.98 (s, 1H).

b) Methyl 4-(6-bromo(2-pyridyl))-5-methylthiothiophene-2-carboxylate:Methyl4-(1,1-dimethyl-1-stannaethyl)-5-methylthiothiophene-2-carboxylate (195mg, 0.56 mmol) as prepared in previous step, and 2,6-dibromopyridine(398 mg, 1.7 mmol) were taken in anhydrous DMF (2 mL). To this mixturetetrakistriphenylphosphine-palladium (20 mg) was added and heated at120° C. for 24 h. DMF was removed under vacuum and the residue waspurified by preparative silica gel thin -layer chromatography to give 78mg (41%) of methyl4-(6-bromo(2-pyridyl))-5-methylthiothiophene-2-carboxylate as a solid.¹H-NMR (CDCl₃; 300 MHz) δ 2.60 (s, 3H), 3.78 (s, 3H), 7.19 (s, 1H), 7.47(dd, J=1.1 and 7.7 Hz, 1H), 7.58 (t, J=7.7, 1H), 7.65 (dd, J=1.1 and 7.4Hz, 1H).

c) Methyl 5-methylthio-4-(6-phenyl(2-pyridyl))thiophene-2-carboxylate:Methyl 4-(6-bromo(2-pyridyl))-5-methylthiothiophene-2-carboxylate (78mg, 0.23 mmol) as prepared in previous step, phenylboronic acid (33 mg,0.27 mmol) and tetrakistriphenylphosphine-palladium (10 mg) were takenin DMF (1 mL). To this solution K₂CO₃ (75 mg, 0.54 mmol) and H₂O (0.3mL) were added and the mixture. was stirred and heated at 90° C. for 18h. Solvents were removed under vacuum and the residue was dissolved inEtOAc and extracted with H₂O, washed with saturated NaCl and dried overanhydrous Na₂SO₄. Thin-layer chromatography of the aqueous layerindicated the presence of some hydrolyzed product. Therefore the aqueouslayer was separated acidified with 10% HCl and extracted with EtOAc. TheEtOAc layer was washed with saturated NaCl and dried over anhydrousNa₂SO₄. This second EtOAc fraction was evaporated and the residue wasdissolved in MeOH and treated with trimethylsilyldiazomethane (1.2 eq).This methanolic solution and the first EtOAc fraction were combined andevaporated. The residue was subjected to preparative thin-layerchromatography (10% EtOAc in Hexane) to give 40 mg (51%) of methyl5-methylthio-4-(6-phenyl(2-pyridyl))thiophene-2-carboxylate which wasused directly in the next step.

d) 5-Methylthio-4-(6-phenyl(2-pyridyl))thiophene-2-carboxamidine: Methyl5-methylthio-4-(6-phenyl(2-pyridyl))thiophene-2-carboxylate (40 mg, 0.12mmol) as prepared in previous step was treated in a manner similar tothat for Example 1, to give 10 mg of5-methylthio-4-(6-phenyl(2-pyridyl))thiophene-2-carboxamidine as asolid. ¹H-NMR (CD₃OD; 300 MHz) δ 2.69 (s, 3H), 7.45-7.60 (m, 3H), 7.62(s, 1H), 7.79 (dd, J=0.9 and 7.8 Hz, 1H), 7.96 (dd, J=0.9 and 8.0 Hz,1H), 8.03-8.12 (m, 3H). Mass spectrum (ESI, m/z): Calcd. for C₁₇H₁₅N₃S₂,326.1 (M+H), found 326.1.

EXAMPLE 43 5-Methylthio-4-(3-phenylphenyl)thiophene-2-carboxamidine

a) Methyl 5-methylthio-4-(3-phenylphenyl)thiophene-2-carboxylate: Methyl4-(1,1-dimethyl-1-stannaethyl)-5-methylthiothiophene-2-carboxylate (200mg, 0.57 mmol, as prepared in Example 42, step a) and1-bromo-3-phenylbenzene (266 mg, 1.14 mmol) were taken in anhydrous DMF(2 mL). To this mixture tetrakistriphenylphosphine-palladium (20 mg) wasadded and heated at 120° C. for 24 h. DMF was removed under vacuum andthe residue was purified by preparative silica gel thin -layerchromatography to give 39 mg (20%) methyl5-methylthio-4-(3-phenylphenyl)thiophene-2-carboxylate as a solid.¹H-NMR (CD₃OD; 300 MHz) δ 2.60 (s, 3H), 3.75 (s, 3H), 7.3-7.5 (m, 6H),7.60-7.66 (m, 4H).

b) 5-Methylthio-4-(3-phenylphenyl)thiophene-2-carboxamidine: Methyl5-methylthio-4-(3-phenylphenyl)thiophene-2-carboxylate (35 mg, 0.1 mmol)as prepared in previous step was treated in a manner similar to that forExample 1, to give 17 mg of5-methylthio-4-(3-phenylphenyl)thiophene-2-carboxamidine as a solid.¹H-NMR (CD₃OD; 300 MHz) δ 2.60 (s, 3H), 7.3-7.6 (m, 10H). Mass spectrum(ESI, m/z): Calcd. for C₁₈H₁₆N₂S₂, 325.4 (M+H), found 325.2.

EXAMPLE 445-Methylthio-4-[4-(phenylthiomethyl)(1,3-thiazol-2-yl)]thiophene-2-carboxamidine

a) Methyl5-methylthio-4-[4-(phenylthiomethyl)(1,3-thiazol-2-yl)]thiophene-2-carboxylate:2-Phenylthioacetyl chloride (1.0 g, 5.4 mmol) was treated in a mannersimilar to that for Example 32 step (a) to give2-bromo-1-phenylthiomethylethan-1-one. The dry solid (1.3 g, 5.3 mmol)was dissolved in acetone (25 ml). To this solution5-(methoxycarbonyl)-2-(methylthio)-thiophene-3-thiocarboxamide (1.32 g,5.3 mmol, Maybridge Chemical Co.) was added and heated at reflux for 5h. At this point the solid that precipitated was filtered off and washedwith acetone and dried under vacuum to give 1.5 g (71%) of methyl5-methylthio-4-[4-(phenylthiomethyl)(1,3-thiazol-2-yl)]thiophene-2-carboxylatewhich was used without further purification in the following step.

b)5-Methylthio-4-[4-(phenylthiomethyl)(1,3-thiazol-2-yl)]thiophene-2-carboxamidine:Methyl5-methylthio-4-[4-(phenylthiomethyl)(1,3-thiazol-2-yl)]thiophene-2-carboxylate(1.5 g, 3.8 mmol) as prepared in previous step was treated in a mannersimilar to that for Example 1, however the product was purified bycrystallizing from methanol to give 0.86 g (60%)5-methylthio-4-[4-(phenylthiomethyl)(1,3-thiazol-2-yl)]thiophene-2-carboxamidineas a solid. ¹H-NMR (DMSO-d₆; 300 MHz) δ 2.72 (s, 3H), 4.38 (s, 2H),7.18-7.39 (m, 5H), 7.57 (s, 1H), 8.46 (s, 1H). Mass spectrum (MALDI-TOF,m/z): Calcd. for C₁₆H₁₅N₃S₄, 378.0 (M+H), found 378.1.

EXAMPLE 454-[4-(2-Chloro-4,5-dimethoxyphenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxamidine

a) Methyl4-[4-(2-chloro-4,5-dimethoxyphenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxylate:2-Chloro-4,5-dimethoxybenzoic acid (0.5 g, 2.3 mmol) and PCl₅ (0.54 g,2.6 mmol) were placed in a round bottomed flask fitted with a refluxcondenser. The mixture was heated in an oil bath at 120° C. for 70 min.The mixture was allowed to cool and the formed phosphorus oxychloridewas removed under vacuum to give 0.52 g (96%) of2-chloro-4,5-dimethoxybenzoyl chloride as a solid.2-Chloro-4,5-dimethoxybenzoyl chloride (0.52 g, 2.2 mmol) was treated ina manner similar to that for Example 32 step (a) to give2-bromo-1-(2-chloro-4,5-dimethoxyphenyl)ethan-1-one. The dry solid (0.65g, 2.2 mmol) was dissolved in acetone (25 ml). To this solution5-(methoxycarbonyl)-2-(methylthio)-thiophene-3-thiocarboxamide (0.55 g,2.2 mmol) was added and heated at reflux for 5 h. At this point thesolid that precipitated was filtered off and washed with acetone anddried under vacuum to give 0.53 g (54%) of methyl4-[4-(2-chloro-4,5-dimethoxyphenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxylate.¹H-NMR (DMSO-d₆; 300 MHz) δ 2.73 (s, 3H), 3.83 (s, 3H), 3.84 (s, 3H),3.85 (s, 3H), 7.13 (s, 1H), 7.69 (s, 1H), 8.13 (s, 1H), 8.17 (s, 1H).

b)4-[4-(2-Chloro-4,5-dimethoxyphenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxamidine:Methyl4-[4-(2-chloro-4,5-dimethoxyphenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxylate(0.53 g, 1.2 mmol) as prepared in previous step was treated in a mannersimilar to that for Example 1, however the product was purified bycrystallizing from methanol to give to give 0.3 g (60%)4-[4-(2-chloro-4,5-dimethoxyphenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxamidineas a solid. ¹H-NMR (DMSO-d₆; 300 MHz) δ 2.77 (s, 3H), 3.84 (s, 6H), 7.13(s, 1H), 7.71 (s, 1H), 8.17 (s, 1H), 8.69 (s, 1H), 9.16 (broad s, 2H),9.48 (broad s, 2H). Mass spectrum (MALDI-TOF, m/z): Calcd. forC₁₇H₁₆N₃O₂S₃Cl, 426.0 (M+H), found 426.6.

EXAMPLE 464-[(Methylethyl)sulfonyl]-5-methylthiothiophene-2-carboxamidine

Methyl 4-[(methylethyl)sulfonyl]-5-methylthiothiophene-2-carboxylate(100 mg, Maybridge Chemical Company, Cornwall, UK) was treated in amanner similar to that for Example 1, to give 50 mg of4-[(methylethyl)sulfonyl]-5-methylthiothiophene-2-carboxamidine. ¹H-NMR(DMSO-d₆; 300 MHz) δ 1.21 (d, J=6.77 Hz, 6H), 2.66 (s, 3H), 3.55 (m,1H), 7.85 (s, 1H. Mass spectrum (MALDI-TOF, CHCA matrix, m/z): Calcd.for C₉H₁₄N₂O₂S₃, 279.0 (M+H), found 279.3.

EXAMPLE 47 Methyl2-{3-[2-(5-amidino-2-methylthio-3-thienyl)-1,3-thiazol-4-yl]phenoxy}acetateTrifluoroacetate

To a solution of 42 mg (0.094 mmol) of(tert-butoxy)-N-({4-[4-(3-hydroxyphenyl)(1,3-thiazol-2-yl)]-5-methylthio(2-thienyl)}iminomethyl)carboxamide,prepared in a manner similar to Example 40, step (c), in 2 mL ofanhydrous N′N′-dimethylformamide (DMF) was added potassium iodide (0.006mmol, 1 mg, Aldrich Chemical Co.), cesium carbonate (0.187 mmol, 61 mg,Aldrich Chemical Co.), and methyl bromoacetate (0.187 mmol, 18 μL,Aldrich Chemical Co.) and heated to 60° C. overnight. The reactionsolution was concentrated and purified on a 1 mm silica prep plateeluting with 3% methanol/CH₂Cl₂ to afford 11 mg (23% yield) of methyl2-{3-[2-(5-{[(tert-butoxy)carbonylamino]iminomethyl}-2-methylthio-3-thienyl)-1,3-thiazol-4-yl]phenoxy}acetatewhich was then subjected to a solution of 50% trifluoracetic acid/CH₂Cl₂for 1 h then concentrated and triturated with diethyl ether and dried toafford 7 mg (77% yield) of methyl2-{-[2-(5-amidino-2-methylthio-3-thienyl)-1,3-thiazol-4-yl]phenoxy}acetatetrifluoroacetate. ¹H-NMR (CD₃OD; 300 MHz) δ 8.51 (s, 1H), 7.92 (s, 1H),7.66 (m, 2H), 7.34-7.39 (t, 1H), 6.93 (m, 1H), 4.8 (s, 2H) 3.80 (s, 3H),2.78 (s, 3H). Mass Spectrum (LC-Q ESI, m/z) Calcd. for C₁₈H₁₇N₃O₃S₃:419.5 (M+H), found 420.3.

EXAMPLE 485-Methylthio-4-[4-(3-{[N-benzylcarbamoyl]methoxy}phenyl)(1,3-thiazol-2-yl)]thiophene-2-carboxamidineTrifluoroacetate

100 mg (0.197 mmol) of2-{3-[2-(5-{[(tert-butoxy)carbonylamino]iminomethyl}-2-methylthio-3-thienyl)-1,3-thiazol-4-yl]phenoxy}aceticacid, as prepared in the previous step, were dissolved in 1 mL ofanhydrous DMF and PyBOP (0.396 mmol, 206 mg), benzylamine (0.396 mmol,42 mg), and diisopropylethylamine (0.494 mmol; 86 μL) were added to thesolution and stirred for 18 hrs after which the solution wasconcentrated and purified on a 2 g silica SPE column and deprotectedwith 50% trifluoroacetic acid/methylene chloride to afford 60 mg (67%yield) of5-methylthio-4-[4-(3-{[N-benzylcarbamoyl]methoxy}phenyl)(1,3-thiazol-2-yl)]thiophene-2-carboxamidinetrifluoroacetate. ¹H-NMR (CDCl₃/TFA-d; 300 MHz) δ 8.97 (s, 1H), 7.86 (s,1H, 7.53 (t, 1H), 7.33 (m, 7H), 7.17 (d, 1H), 4.79 (s, 2H) 4.59 (s, 2H),2.95 (s, 3H). Mass Spectrum (ESI, m/z) Calcd. for C₂₄H₂₂N₄O₂S₃: 494.6(M+H), found 495.2.

EXAMPLE 494-{4-[3-({N-[(3,4-Dimethoxyphenyl)methyl]carbamoyl}methoxy)phenyl](1,3-thiazol-2-yl)}-5-methylthiophene-2-carboxamidineTrifluoroacetate

Dissolved 100 mg (0.197 mmol) of2-{3-[2-(5-{[(tert-butoxy)carbonylamino]iminomethyl}-2-methylthio-3-thienyl)-1,3-thiazol-4-yl]phenoxy}aceticacid, prepared in a manner similar to Example 48, step (c), in 1 mL ofanhydrous DMF and added PyBOP (0.396 mmol, 206 mg),3,4-dimethoxybenzylamine (0.396 mmol, 66 mg), and diisopropylethylamine(0.494 mmol; 86 μL) and let stir for 18 hrs after which solution wasconcentrated and purified on a 2 g silica SPE column and deprotectedwith 50% trifluoroacetic acid/methylene chloride to afford 45 mg (41%yield)4-{4-[3-({N-[(3,4-dimethoxyphenyl)methyl]carbamoyl}methoxy)phenyl](1,3-thiazol-2-yl)}-5-methylthiothiophene-2-carboxamidinetrifluoroacetate. ¹H-NMR (CDCl₃/TFA-d; 300 MHz) δ 8.48 (s, 1H), 7.78 (s,1H), 7.72 (m, 1H), 7.66 (d, 1H), 7.39 (t, 1H), 7.02 (d, 1H) 4.68 (s,2H), 4.43 (s, 2H), 3.75 (s, 3H). 3.56 (s, 3H). 2.78 (s, 3H). MassSpectrum (LC-Q ESI, m/z) Calcd. for C₂₆H₂₆N₄O₄S₃: 554.6 (M+H), found555.2

EXAMPLE 505-Methylthio-4-{4-[3-({N-[2-(phenylamino)ethyl]carbamoyl}methoxy)phenyl](1,3-thiazol-2-yl)}thiophene-2-carboxamidineTrifluoroacetate

Dissolved 100 mg (0.197 mmol) of2-{3-[2-(5-{[(tert-butoxy)carbonylamino]iminomethyl}-2-methylthio-3-thienyl)-1,3-thiazol-4-yl]phenoxy}aceticacid, prepared in a manner similar to Example 48, step (c), in 1 mL ofanhydrous DMF and added PyBOP (0.396 mmol, 206 mg),N-phenylethylenediamine (0.396 mmol, 54 mg), and diisopropylethylamine(0.494 mmol; 86 μL) and let stir for 18 hrs after which solution wasconcentrated and purified on a 2 g silica SPE column and deprotectedwith 50% trifluoroacetic acid/methylene chloride to afford 65 mg (63%yield)5-methylthio-4-{4-[3-({N-[2-(phenylamino)ethyl]carbamoyl}methoxy)phenyl](1,3-thiazol-2-yl)}thiophene-2-carboxamidinetrifluoroacetate ¹H-NMR (CDCl₃/TFA-d; 300 MHz) δ 8.50 (s, 1H), 7.82 (s,1H), 7.77 (s, 1H), 7.66 (d, 1H), 7.39 (t, 1H), 7.02 (d, 1H) 4.68 (s,2H), 4.43 (s, 2H), 3.75 (s, 3H). 3.56 (s, 3H). 2.78 (s, 3H). MassSpectrum (LC-Q ESI, m/z) Calcd. for C₂₅H₂₅N₅O₂S₃: 523.6 (M+H), found524.1

EXAMPLE 515-Methylthio-4-[4-(3-{[N-(2-morpholin-4-ylethyl)carbamoyl]methoxy}phenyl)(1,3-thiazol-2-yl)]thiophene-2-carboxamidineTrifluoroacetate

83 mg (0.164 mmol) of2-{3-[2-(5-{[(tert-butoxy)carbonylamino]iminomethyl}-2-methylthio-3-thienyl)-1,3-thiazol-4-yl]phenoxy}aceticacid, prepared in a manner similar to Example 40, step (c), was reactedwith 2-morpholin-4-ylethylamine (0.328 mmol, 43 μL) in a manner similarto Example 48 to afford 46 mg (54% yield) of5-methylthio-4-[4-(3-{[N-(2-morpholin-4-ylethyl)carbamoyl]methoxy}phenyl)(1,3-thiazol-2-yl)]thiophene-2-carboxamidinetrifluoroacetate. ¹H-NMR (DMSO-d₆, 300 MHz) δ 9.38 (bs, 2H), 9.08 (bs,2H), 8.61 (s, 1H), 8.45 (t, 1H), 8.27 (s, 1H), 7.72 (m, 2H) 7.45 (t,1H), 7.02 (d, J=8 Hz, 1H), 4.62 (s, 2H), 3.53-3.64 (m, 5H), 3.24-3.38(m, 5H), 2.80 (s, 3H), 1.1 (t, 2H). Mass Spectrum (ESI, m/z) Calcd. forC₂₃H₂₇N₅O₃S₃: 517.6 (M+H), found 518.2.

EXAMPLE 525-Methylthio-4-{4-[3-(2-morpholin-4-yl-2-oxoethoxy)phenyl(1,3-thiazol-2-yl)}thiophene-2-carboxamidineTrifluoroacetate

73 mg (0.144 mmol) of2-{3-[2-(5-{[(tert-butoxy)carbonylamino]iminomethyl}-2-methylthio-3-thienyl)-1,3-thiazol-4-yl]phenoxy}aceticacid, prepared in a manner similar to Example 48, step (c), was reactedwith morpholine (0.288 mmol; 25 μL) in a manner similar to Example 48step (b) to afford 50 mg (75% yield)5-methylthio-4-{4-[3-(2-morpholin-4-yl-2-oxoethoxy)phenyl](1,3-thiazol-2-yl)}thiophene-2-carboxamidinetrifluoroacetate. ¹H-NMR (DMSO-d₆/TFA-d; 300 MHz) δ 9.38 (bs, 1H, 9.08(bs, 2H), 8.66 (s, 1H), 8.22 (s, 1H), 7.72 (m, 2H) 7.42 (t, 1H),6.98-7.00 (dd, J=2.3 Hz and 8.2 Hz, 1H), 4.95 (s, 2H), 3.53-3.67 (m,8H), 2.82 (s, 3H). Mass Spectrum (ESI, m/z) Calcd. for C₂₁H₂₂N₄O₃S₃:474.6 (M+H), found 475.2.

EXAMPLE 535-Methylthio-4-{4-[3-(2-oxo-2-piperazinylethoxy)phenyl](1,3-thiazol-2-yl)}thiophene-2-carboxamidineTrifluoroacetate

100 mg (0.198 mmol) of2-{3-[2-(5-{[(tert-butoxy)carbonylamino]iminomethyl}-2-methylthio-3-thienyl)-1,3-thiazol-4-yl]phenoxy}aceticacid, prepared in a manner similar to Example 48, step (c), was reactedwith tert-butyl piperazinecarboxylate (0.396 mmol; 74 mg) in a mannersimilar to Example 48, step (b) to afford 40 mg (43% yield) of5-methylthio-4-{4-[3-(2-oxo-2-piperazinylethoxy)phenyl](1,3-thiazol-2-yl)}thiophene-2-carboxamidinetrifluoroacetate. ¹H-NMR (DMSO-d₆/TFA-d; 300 MHz) δ 8.68 (s, 1H),8.20(s, 1H), 7.75 (m, 2H) 7.43 (t, 1H), 7.01 (dd, J=2.3 Hz and 8.1 Hz,1H), 5.02 (s, 2H), 3.76 (bs, 4H), 3.17-3.26 (m 4H). 2.82 (s, 3H). MassSpectrum (LC-Q ESI, m/z) Calcd. for C₂₁H₂₃N₅O₂S₃: 473.6 (M+H), found474.2.

EXAMPLE 544-[4-(3-{[N-(2-Aminoethyl)carbamoyl]methoxy}phenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxamidineHydrochloride

51 mg (0.101 mmol) of2-{3-[2-(5-{[(tert-butoxy)carbonylamino]iminomethyl}-2-methylthio-3-thienyl)-1,3-thiazol-4-yl]phenoxy}aceticacid, prepared in a manner similar to Example 48, step (c), was reactedwith N-(2-aminoethyl)(tert-butoxy)carboxamide (0.202 mmol; 32 mg) in amanner similar to Example 48, step (b) to afford 80 mg (80% yield) of4-(4-{3-[(N-{2-[(tert-butoxy)carbonylamino]ethyl}carbamoyl)methoxy]phenyl}(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxamidinewhich was then deprotected with 4N HCl in dioxane to afford 36 mg (68%yield) of4-[4-(3-{[N-(2-aminoethyl)carbamoyl]methoxy}phenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxamidinehydrochloride. ¹H-NMR (CD₃OD; 300 MHz) δ 8.55 (s, 1H), 7.95 (s, 1H),7.73 (m, 2H) 7.41 (t, 1H), 7.05 (m, 1H), 4.80 (s, 2H), 3.51 (m, 2H),3.13-3.31 (m, 2H), 2.83 (s, 3H). Mass Spectrum (ESI, m/z) Calcd. forC₁₉H₂₁N₅O₂S₃: 447.5 (M+H), found 448.2.

EXAMPLE 554-(4-{3-[2-(4-Acetylpiperazinyl)-2-oxoethoxy]phenyl}(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxamidineTrifluoroacetate

52 mg (0.103 mmol) of2-{3-[2-(5-{[(tert-butoxy)carbonylamino]iminomethyl}-2-methylthio-3-thienyl)-1,3-thiazol-4-yl]phenoxy}aceticacid, prepared in a manner similar to Example 48, step (c), was reactedwith 1-acetyl piperazine (0.154 mmol, 20 mg),1-hydroxy-7-azabenzotriazole (HOAt)) (0.154 mmol, 21 mg),O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate) HATU (0.154 mmol, 58 mg) and diisopropylethylamine(0.258 mmol, 44 μL) in DMF to afford crude product which was thenpurified on 1 mm silica prep plates eluting with 3% methanol/methylenechloride to afford 28 mg (53% yield) ofN-{[4-(4-{3-[2-(4-acetylpiperazinyl)-2-oxoethoxy]phenyl}(1,3-thiazol-2-yl))-5-methylthio(2-thienyl)]iminomethyl}(tert-butoxy)carboxamide.This was subsequently reacted with a solution of trifluoroacetic acid:methylene chloride: water (47.5%: 47.5%: 2.5%) for 1 hour, concentratedand purified on a silica SPE column eluting with 15% methanol/methylenechloride to afford 20 mg (80% yield) of4-(4-{3-[2-(4-acetylpiperazinyl)-2-oxoethoxy]phenyl}(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxamidinetrifluoroacetate. ¹H-NMR (CD₃OD; 300 MHz) δ 8.48 (s, 1H), 7.91 (s, 1H),7.69 (m, 2H) 7.38 (t, 1H), 6.99 (dd, J=2 Hz and 8.1 Hz, 1H), 4.93 (s,21H), 3.52-3.67 (m, 8H), 2.78 (s, 3H), 2.12 (s, 3H). Mass Spectrum (ESI,m/z) Calcd. for C₂₃H₂₅N₅O₃S₃: 515.6 (M+H), found 516.2.

EXAMPLE 564-(4-{3-[2-(4-Methylpiperazinyl)-2-oxoethoxy]phenyl}(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxamidineTrifluoroacetate

54 mg (0.107 mmol) of2-{3-[2-(5-{[(tert-butoxy)carbonylamino]iminomethyl}-2-methylthio-3-thienyl)-1,3-thiazol-4-yl]phenoxy}aceticacid, prepared in a manner similar to Example 48, step (c), was reactedwith N-methyl piperazine (0.128 mmol, 14 μL),1-hydroxy-7-azabenzotriazole (HOAt) (0.128 mmol, 17 mg),O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate) HATU (0.128 mmol, 49 mg) and diisopropylethylamine(0.268 mmol, 56 μL) in DMF to afford crude product which was thenpartitioned between methylene chloride and 1N NaOH and washed. Theorganic layer was obtained and similarly washed with 10% citric acid andsaturated aq. sodium chloride, dried over sodium sulfate andconcentrated to a yellow oil. The oil was then purified on 1 mm silicaprep plates eluting with 5% methanol/methylene chloride to afford(tert-butoxy)-N-{imino[4-(4-{3-[2-(4-methylpiperazinyl)-2-oxoethoxy]phenyl}(1,3-thiazol-2-yl))-5-methylthio(2-thienyl)]methyl}carboxamide.This was subsequently reacted with a solution of trifluoroacetic acid:methylene chloride: water (47.5%: 47.5%: 2.5%) for 1 hour, concentratedand purified on a silica SPE column eluting with 10-15%methanol/methylene chloride to afford 17 mg (33% yield) of4-(4-{3-[2-(4-methylpiperazinyl)-2-oxoethoxy]phenyl}(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxamidinetrifluoroacetate. ¹H-NMR (CD₃OD; 300 MHz) δ 8.52 (s, 1H), 7.91 (s, 1H),7.69 (m, 2H), 7.38 (t, 1H), 6.98 (dd, J=2.0 Hz and 8.1 Hz, 1H), 4.90 (s,2H), 3.66 (t, 4H), 2.78 (s, 3H), 2.49-2.57 (m, 4H), 2.35 (s, 3H). MassSpectrum (ESI, m/z) Calcd. for C₂₂H₂₅N₅O₂S₃: 487.6 (M+H), found 488.2

EXAMPLE 575-Methylthio-4-[4-(3-{2-oxo-2-[4-benzylpiperaziny]ethoxy}phenyl)(1,3-thiazol-2-yl)]thiophene-2-carboxamidineTrifluoroacetate

54 mg (0.107 mmol) of2-{3-[2-(5-{[(tert-butoxy)carbonylamino]iminomethyl}-2-methylthio-3-thienyl)-1,3-thiazol-4-yl]phenoxy}aceticacid, prepared in a manner similar to Example 48, step (c), was reactedwith N-benzylpiperazine (0.128 mmol, 22 μL),1-hydroxy-7-azabenzotriazole (HOAt) (0.128 mmol, 17 mg),O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate) HATU (0.128 mmol, 48 mg) and diisopropylethylamine(0.267 mmol, 50 μL) in DMF to afford crude product which was thenpartitioned between methylene chloride and 1N NaOH and washed. Theorganic layer was obtained and similarly washed with 10% citric acid andsaturated aq. sodium chloride, dried over sodium sulfate andconcentrated to a yellow oil. The oil was then purified on 11 mm silicaprep plates eluting with 5% methanol/methylene chloride to afford(tert-butoxy)-N-(imino{5-methylthio-4-[4-(3-{2-oxo-2-[4-benzylpiperaziny]ethoxy}phenyl)(1,3-thiazol-2-yl)](2-thienyl)}methyl)carboxamide.This was subsequently reacted with a solution of trifluoroacetic acid:methylene chloride: water (47.5%: 47.5%: 2.5%) for 1 hour, concentratedand purified on a 5 g silica SPE column eluting with 10-15%methanol/methylene chloride to afford 36 mg (60% yield) of5-methylthio-4-[4-(3-{2-oxo-2-[4-benzylpiperazinyl]ethoxy}phenyl)(1,3-thiazol-2-yl)]thiophene-2-carboxamidinetrifluoroacetate. ¹H-NMR (CD₃OD; 300 MHz) δ 8.54 (s, 1H), 7.93 (s, 1H),7.71 (m, 2H), 7.50 (s, 5H) 7.39 (t, 1H), 6.99 (dd, J=2 Hz and 8.1 Hz,1H), 4.94 (s, 2H), 4.37 (s, 2H), 3.3 (m, 4H), 2.81 (s, 3H), 2.49-2.57(m, 4H), 2.35 (s, 3H). Mass (ESI, m/z) Calcd. for C₂₈H₂₉N₅O₂S₃: 563.7(M+H), found 564.3.

EXAMPLE 58(D,L)-4-(4-{3-[2-(3-Aminopyrrolidinyl)-2-oxoethoxy]phenyl}(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxamidineTrifluoroacetate

41 mg (0.081 mmol) of2-{3-[2-(5-{[(tert-butoxy)carbonylamino]iminomethyl}-2-methylthio-3-thienyl)-1,3-thiazol-4-yl]phenoxy}aceticacid, prepared in a manner similar to Example 48, step (c), was reactedwith (D,L) (tert-butoxy)-N-pyrrolidin-3-ylcarboxamide (0.122 mmol, 23mg), O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate) HATU (0.122 mmol, 46 mg),1-hydroxy-7-azabenzotriazole (HOAt) (0.122 mmol, 17 mg) anddiisopropylethylamine (0.203 mmol, 35 μL) in a manner similar to Example56 to afford 20 mg (53% yield) of(D,L)-4-(4-{3-[2-(3-aminopyrrolidinyl)-2-oxoethoxy]phenyl}(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxamidinetrifluoroacetate. ¹H-NMR (CD₃OD; 300 MHz) δ 8.54 (s, 1H), 7.94 (s, 1H),7.71 (m, 2H), 7.39 (t, 1H), 6.99 (dd, J=2.0 Hz and 8.1 Hz, 1H), 4.85 (s,2H), 4.37 (s, 2H), 3.60-4.01 (m, 5H), 2.81 (s, 3H), 2.15-2.71 (m, 2H).Mass Spectrum (ESI, m/z) Calcd. for C₂₁H₂₃N₅O₂S₃: 473.6 (M+H), found474.3.

EXAMPLE 595-Methylthio-4-{4-]3-(2-oxo-2-piperidylethoxy)phenyl](1,3-thiazol-2-yl)}thiophene-2-carboxamidineTrifluoroacetate

33 mg (0.065 mmol) of2-{3-[2-(5-{[(tert-butoxy)carbonylamino]iminomethyl}-2-methylthio-3-thienyl)-1,3-thiazol-4-yl]phenoxy}aceticacid, prepared in a manner similar to Example 40, step (c), was reactedwith piperidine (0.078 mmol, 8 μL),O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate) HATU (0.078 mmol, 30 mg),1-hydroxy-7-azabenzotriazole (HOAt) (0.078 mmol, 11 mg) anddiisopropylethylamine (0.163 mmol, 56 μL) in a manner similar to Example57 to afford 15 mg (41% yield) of5-methylthio-4-{4-[3-(2-oxo-2-piperidylethoxy)phenyl](1,3-thiazol-2-yl)}thiophene-2-carboxamidinetrifluoroacetate. ¹H-NMR (CD₃OD; 300 MHz) δ 8.54 (s, 1H), 7.92 (s, 1H),7.69 (m, 2H), 7.35-7.40 (t, 1H), 6.98 (dd, J=2 Hz and 8.1 Hz, 1H), 4.95(s, 2H), 3.52-3.60 (m, 4H), 2.80 (s, 3H), 1.57-1.70 (m, 6H). MassSpectrum (ESI, m/z) Calcd. for C₂₂H₂₄N₄O₂S₃: 472.6 (M+H), found 473.2.

EXAMPLE 602-(3-{2-[5-(Imino{[(4-polystyryloxyphenyl)methoxy]carboxylamino}methyl)-2-methylthio-3-thienyl]-1,3-thiazol-4-yl}phenoxy)aceticAcid

2 g (1.86 mmol) of p-nitrophenyl carbonate Wang resin (0.93 mmol/g)(Calbiochem-Novabiochem, San Diego, Calif.) was suspended in 9 mL of a2:1 mixture of anhydrous DMSO:DMF. 2 g (4.93 mmol) of2-{3-[2-(5-amidino-2-methylthio-3-thienyl)-1,3-thiazol-4-yl]phenoxy}aceticacid was added to suspension followed by the addition of 1 mL of1,8-diazabicyclo[5.4.0]undec-7-ene, (DBU, 6.69 mmol) and let shakevigorously for 5 days after which resin was washed thoroughly with DMF,MeOH, and diethyl ether and dried in vacuo to afford 2 g of resin-bound2-{3-[2-(5-amidino-2-methylthio-3-thienyl)-1,3-thiazol-4-yl]phenoxy}aceticacid.

EXAMPLE 61 (D,L)-Ethyl1-(2-{3-[2-(5-amidino-2-methylthio-3-thienyl)-1,3-thiazol-4-yl]phenoxy}acetyl)piperidine-2-carboxylateTrifluoroacetate

100 mg (0.093 mmol) of resin-bound2-{3-[2-(5-amidino-2-methylthio-3-thienyl)-1,3-thiazol-4-yl]phenoxy}aceticacid (0.93 mmol/g), as prepared in a manner similar to Example 60, wassuspended 1 mL of anhydrous DMF.O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate) HATU (0.5 M, 190 mg), 1-hydroxy-7-azabenzotriazole(HOAt) (0.5 M; 68 mg), ethyl piperidine-2-carboxylate (0.5 M; 78 μL) anddiisopropylethylamine (0.233 mmol, 40 μL) were added and allowed toshake vigorously for 18 hrs, after which the resin was washed thoroughlywith DMF, methanol, methylene chloride, and diethyl ether. After drying,crude product was removed from resin by reaction with a solution oftrifluoroacetic acid: methylene chloride: water (47.5%: 47.5%: 2.5%) for1 hour. The solution was filtered and concentrated to a yellow oil.After purification on a 2 g silica SPE column, eluting with a gradientof 3%-10% MeOH/methylene chloride, 15 mg (30% yield) of (D,L)-ethyl1-(2-{3-[2-(5-amidino-2-methylthio-3-thienyl)-1,3-thiazol-4-yl]phenoxy}acetyl)piperidine-2-carboxylatetrifluoroacetate was obtained. Mass Spectrum (ESI, m/z) Calcd. forC₂₅H₂₈N₄O₄S₃: 544.70 (M+H), found 545.2

EXAMPLE 625-Methylthio-4-{4-[3-(2-oxo-2-pyrrolidinylethoxy)phenyl](1,3-thiazol-2-yl)}thiophene-2-carboxamidineTrifluoroacetate

100 mg (0.093 mmol) of resin-bound2-{3-[2-(5-amidino-2-methylthio-3-thienyl)-1,3-thiazol-4-yl]phenoxy}aceticacid (0.93 mmol/g), as prepared in a manner similar to Example 60, wassuspended 1 mL of anhydrous DMF.O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate) HATU (0.5 M, 190 mg), 1-hydroxy-7-azabenzotriazole(HOAt) (0.5 M; 68 mg), pyrrolidine (0.5 M; 42 μL) anddiisopropylethylamine (0.233 mmol, 40 μL) were added and allowed toshake vigorously for 18 hours, after which the resin was washedthoroughly with DMF, methanol, methylene chloride, and diethyl ether.After drying, crude product was removed from resin by reaction with asolution of trifluoroacetic acid: methylene chloride: water (47.5%:47.5%: 2.5%) for 1 hour. After trituration with diethyl ether anddrying, 18 mg (42% yield) of5-methylthio-4-{4-[3-(2-oxo-2-pyrrolidinylethoxy)phenyl](1,3-thiazol-2-yl)}thiophene-2-carboxamidinetrifluoroacetate was obtained. Mass Spectrum (ESI, m/z) Calcd. forC₂₁H₂₂N₄O₂S₃: 458.6 (M+H), found 459.2

EXAMPLE 635-Methylthio-4-[4-(3-{2-oxo-2-[4-benzylpiperidyl]ethoxy}phenyl)(1,3-thiazol-2-yl)]thiophene-2-carboxamidineTrifluoroacetate

80 mg (0.074 mmol) of resin-bound2-{3-[2-(5-amidino-2-methylthio-3-thienyl)-1,3-thiazol-4-yl]phenoxy}aceticacid (0.93 mmol/g), as prepared in a manner similar to Example 60, wassuspended in 1 mL of anhydrous DMF.O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate) HATU (0.5 M, 190 mg), 1-hydroxy-7-azabenzotriazole(HOAt) (0.5 M; 68 mg), 4-benzyl piperidine (0.5 M; 88 μL) anddiisopropylethylamine (0.185 mmol, 32 μL) were added and allowed toshake vigorously for 18 hrs, after which the resin was washed thoroughlywith DMF, methanol, methylene chloride, and diethyl ether. After drying,crude product was removed from resin by reaction with a solution oftrifluoroacetic acid: methylene chloride: water (47.5%: 47.5%: 2.5%) for1 hour. After trituration with diethyl ether and drying, 17 mg (40%yield) of5-methylthio-4-[4-(3-{2-oxo-2-[4-benzylpiperidyl]ethoxy}phenyl)(1,3-thiazol-2-yl)]thiophene-2-carboxamidinetrifluoroacetate was obtained. Mass Spectrum (ESI, m/z) Calcd. forC₂₉H₃₀N₄O₂S₃: 562.7 (M+H), found 563.3.

EXAMPLE 64(D,L)-4-(4-{3-[2-(3-Methylpiperidyl)-2-oxoethoxy]phenyl}(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxamidineTrifluoroacetate

80 mg (0.074 mmol) of resin-bound2-{3-[2-(5-amidino-2-methylthio-3-thienyl)-1,3-thiazol-4-yl]phenoxy}aceticacid (0.93 mmol/g), as prepared in a manner similar to Example 60, wasreacted with (+/−)-3-methyl piperidine (0.5 M, 59 μL) andO-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate) HATU (0.5 M, 190 mg), 1-hydroxy-7-azabenzotriazole(HOAt) (0.5 M; 68 mg) and diisopropylethylamine (0.185 mmol, 32 μL) in 1mL of anhydrous DMF in a manner similar to Example 63 to afford 10 mg(28% yield) of4-(4-{3-[2-(3-methylpiperidyl)-2-oxoethoxy]phenyl}(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxamidinetrifluoroacetate. Mass Spectrum (ESI, m/z) Calcd. for C₂₃H₂₆N₄O₂S₃:486.6 (M+H), found 487.3.

EXAMPLE 654-(4-{3-[2-(4-Methylpiperidyl)-2-oxoethoxy]phenyl}(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxamidineTrifluoroacetate

80 mg (0.074 mmol) of resin-bound2-{3-[2-(5-amidino-2-methylthio-3-thienyl)-1,3-thiazol-4-yl]phenoxy}aceticacid (0.93 mmol/g), as prepared in a manner similar to Example 60, wasreacted with 4-methyl piperidine (0.5 M, 59 μL) andO-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate) HATU (0.5 M, 190 mg), 1-hydroxy-7-azabenzotriazole(HOAt) (0.5 M; 68 mg) and diisopropylethylamine (0.185 mmol, 32 μL) in 1mL of anhydrous DMF in a manner similar to Example 63 to afford 12 mg(33% yield) of4-(4-{3-[2-(4-methylpiperidyl)-2-oxoethoxy]phenyl}(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxamidinetrifluoroacetate. Mass Spectrum (ESI, m/z) Calcd. for C₂₃H₂₆N₄O₂S₃:486.6 (M+H), found 487.3.

EXAMPLE 664-(4-{3-[2-(2-Azabicyclo[4.4.0]dec-2-yl)-2-oxoethoxy]phenyl}(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxamidineTrifluoroacetate

80 mg (0.074 mmol) of resin-bound2-{3-[2-(5-amidino-2-methylthio-3-thienyl)-1,3-thiazol-4-yl]phenoxy}aceticacid (0.93 mmol/g), as prepared in a manner similar to Example 60, wasreacted with decahydroquinoline (0.5 M, 75 μL) andO-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate) HATU (0.5 M, 190 mg), 1-hydroxy-7-azabenzotriazole(HOAt) (0.5 M; 68 mg) and diisopropylethylamine (0.185 mmol, 32 μL) in 1mL of anhydrous DMF in a manner similar to Example 63 to afford 16 mg(41% yield) of4-(4-{3-[2-(2-azabicyclo[4.4.0]dec-2-yl)-2-oxoethoxy]phenyl}(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxamidinetrifluoroacetate. Mass Spectrum (ESI, m/z) Calcd. for C₂₆H₃₀N₄O₂S₃:526.7 (M+H), found 527.2.

EXAMPLE 67 (D,L)-Ethyl1-(2-{3-[2-(5-amidino-2-methylthio-3-thienyl)-1,3-thiazol-4-yl]phenoxy}acetyl)piperidine-3-carboxylateTrifluoroacetate

80 mg (0.074 mmol) of resin-bound2-{3-[2-(5-amidino-2-methylthio-3-thienyl)-1,3-thiazol-4-yl]phenoxy}aceticacid (0.93 mmol/g), as prepared in a manner similar to Example 60, wasreacted with ethyl nipecotate (0.5 M, 78 μL) andO-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate) HATU (0.5 M, 190 mg), 1-hydroxy-7-azabenzotriazole(HOAt) (0.5 M, 68 mg) and diisopropylethylamine (0.185 mmol, 32 μL) in 1mL of anhydrous DMF in a manner similar to Example 63 to afford 18 mg(45% yield) of ethyl1-(2-{3-[2-(5-amidino-2-methylthio-3-thienyl)-1,3-thiazol-4-yl]phenoxy}acetyl)piperidine-3-carboxylatetrifluoroacetate. Mass Spectrum (ESI, m/z) Calcd. for C₂₅H₂₈N₄O₄S₃:545.7 (M+H), found 545.2.

EXAMPLE 685-Methylthio-4-{4-[3-(2-oxo-2-(1,2,3,4-tetrahydroquinolyl)ethoxy)phenyl](1,3-thiazol-2-yl)}thiophene-2-carboxamidineTrifluoroacetate

100 mg (0.093 mmol) of resin-bound2-{3-[2-(5-amidino-2-methylthio-3-thienyl)-1,3-thiazol-4-yl]phenoxy}aceticacid (0.93 mmol/g), as prepared in a manner similar to Example 60, wasreacted with 1,2,3,4-tetrahydroisoquinoline (0.5M) andO-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate) HATU (0.5 M, 190 mg), 1-hydroxy-7-azabenzotriazole(HOAt) (0.5 M; 68 mg) and diisopropylethylamine (0.233 mmol, 40 μL) in 1mL of anhydrous DMF in a manner similar to Example 63 to afford 20 mg(42% yield) of5-methylthio-4-{4-[3-(2-oxo-2-(1,2,3,4-tetrahydroquinolyl)ethoxy)phenyl](1,3-thiazol-2-yl)}thiophene-2-carboxamidinetrifluoroacetate. Mass Spectrum (ESI, m/z) Calcd. for C₂₆H₂₄N₄O₂S₃:520.7 (M+H), found 521.2.

EXAMPLE 69 Ethyl1-(2-{3-[2-(5-amidino-2-methylthio-3-thienyl)-1,3-thiazol-4-yl]phenoxy}acetyl)piperidine-4-carboxylateTrifluoroacetate

100 mg (0.093 mmol) of resin-bound2-{3-[2-(5-amidino-2-methylthio-3-thienyl)-1,3-thiazol-4-yl]phenoxy}aceticacid (0.93 mmol/g), as prepared in a manner similar to Example 60, wasreacted with ethyl isonipecotate (0.5 M, 77 mg) andO-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate) HATU (0.5 M, 190 mg), 1-hydroxy-7-azabenzotriazole(HOAt) (0.5 M; 68 mg) and diisopropylethylamine (0.233 mmol, 40 μL) in 1mL of anhydrous DMF in a manner similar to Example 63 to afford 21 mg(42% yield) of ethyl1-(2-{3-[2-(5-amidino-2-methylthio-3-thienyl)-1,3-thiazol-4-yl]phenoxy}acetyl)piperidine-4-carboxylatetrifluoroacetate. Mass Spectrum (ESI, m/z) Calcd. for C₂₅H₂₈N₄O₄S₃:545.7 (M+H), found 545.3.

EXAMPLE 704-(4-{3-[2-((3R)-3-Hydroxypiperidyl)-2-oxoethoxy]phenyl}(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxamidineTrifluoroacetate

100 mg (0.093 mmol) of resin-bound2-{3-[2-(5-amidino-2-methylthio-3-thienyl)-1,3-thiazol-4-yl]phenoxy}aceticacid (0.93 mmol/g), as prepared in a manner similar to Example 60, wasreacted with R-(+)-3-hydroxy piperidine (0.5 M, 69 mg) andO-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate) HATU (0.5 M, 190 mg), 1-hydroxy-7-azabenzotriazole(HOAt) (0.5M; 68 mg) and diisopropylethylamine (0.233 mmol, 40 μL) in 1mL of anhydrous DMF in a manner similar to Example 63 to afford 16 mg(36% yield) of4-(4-{3-[2-((3R)-3-hydroxypiperidyl)-2-oxoethoxy]phenyl}(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxamidinetrifluoroacetate. Mass Spectrum (ESI, m/z) Calcd. for C₂₂H₂₃N₄O₃S₃:489.7 (M+H), found 489.2.

EXAMPLE 71D,L-4-(4-{3-[2-(2-Ethylpiperidyl)-2-oxoethoxy]phenyl}(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxamidineTrifluoroacetate

100 mg (0.093 mmol) of resin-bound2-{3-[2-(5-amidino-2-methylthio-3-thienyl)-1,3-thiazol-4-yl]phenoxy}aceticacid (0.93 mmol/g), as prepared in a manner similar to Example 60, wasreacted with 2-ethyl piperidine (0.5M) andO-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate) HATU (0.5 M, 190 mg), 1-hydroxy-7-azabenzotriazole(HOAt) (0.5M; 68 mg) and diisopropylethylamine (0.233 mmol, 40 μL) in 1mL of anhydrous DMF in a manner similar to Example 63 to afford 11 mg(23% yield) ofD,L-4-(4-{3-[2-(2-ethylpiperidyl)-2-oxoethoxy]phenyl}(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxamidinetrifluoroacetate. Mass Spectrum (ESI, m/z) Calcd. for C₂₄H₂₇N₄O₂S₃:501.4 (M+H), found 501.4.

EXAMPLE 724-(4-{3-[2-((3S)-3-Hydroxypyrrolidinyl)-2-oxoethxy]phenyl}(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxamidineTrifluoroacetate

100 mg (0.093 mmol) of resin-bound2-{3-[2-(5-amidino-2-methylthio-3-thienyl)-1,3-thiazol-4-yl]phenoxy}aceticacid (0.93 mmol/g), as prepared in a manner similar to Example 60, wasreacted with R-(−)-3-pyrrolidinol (0.5 M, 62 mg) andO-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate) (HATU, 0.5 M, 190 mg), 1-hydroxy-7-azabenzotriazole(HOAt) (0.5M; 68 mg) and diisopropylethylamine (0.233 mmol, 40 μL) in 1mL of anhydrous DMF in a manner similar to Example 63 to afford 10 mg(23% yield) of4-(4-{3-[2-((3S)-3-hydroxypyrrolidinyl)-2-oxoethoxy]phenyl}(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxamidinetrifluoroacetate. Mass Spectrum (ESI, m/z) Calcd. for C₂₁H₂₂N₄O₃S₃:475.2 (M+H), found 475.2.

EXAMPLE 735-Methylthio-4-(4-{3-[(N-(5,6,7,8-tetrahydronaphthyl)carbamoyl)methoxy]phenyl}(1,3-thiazol-2-yl))thiophene-2-carboxamidineTrifluoroacetate

100 mg (0.093 mmol) of resin-bound2-{3-[2-(5-amidino-2-methylthio-3-thienyl)-1,3-thiazol-4-yl]phenoxy}aceticacid (0.93 mmol/g), as prepared in a manner similar to Example 60, wasreacted with 5,6,7,8-tetrahydro-1-naphthylamine (0.5 M, 73 mg) andO-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate) (HATU, 0.5 M, 190 mg), 1-hydroxy-7-azabenzotriazole(HOAt) (0.5 M; 68 mg) and diisopropylethylamine (0.233 mmol, 40 μL) in 1mL of anhydrous DMF in a manner similar to Example 63 to afford 15 mg(30% yield) of5-methylthio-4-(4-{3-[(N-(5,6,7,8-tetrahydronaphthyl)carbamoyl)methoxy]phenyl}(1,3-thiazol-2-yl))thiophene-2-carboxamidinetrifluoroacetate. Mass Spectrum (ESI, m/z) Calcd. for C₂₇H₂₆N₄O₂S₃:535.2 (M+H), found 535.3.

EXAMPLE 74D,L-4-[4-(3-{2-[3-(Hydroxymethyl)piperidyl]-2-oxoethoxy}phenyl)(1,3-thiazol-2-yl)]-5-methylthiophene-2-carboxamidineTrifluoroacetate

100 mg (0.093 mmol) of resin-bound2-{3-[2-(5-amidino-2-methylthio-3-thienyl)-1,3-thiazol-4-yl]phenoxy}aceticacid (0.93 mmol/g), as prepared in a manner similar to Example 60, wasreacted with 3-piperidine methanol (0.5 M, 58 mg) andO-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate) (HATU, 0.5 M, 190 mg), 1-hydroxy-7-azabenzotriazole(HOAt) (0.5M; 68 mg) and diisopropylethylamine (0.233 mmol, 40 μL in 1mL of anhydrous DMF in a manner similar to Example 40 to afford to 19 mg(40% yield) ofD,L-4-[4-(3-{2-[3-(hydroxymethyl)piperidyl]-2-oxoethoxy}phenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxamidinetrifluoroacetate. Mass Spectrum (ESI, m/z) Calcd. for C₂₃H₂₅N₄O₃S₃:503.2 (M+H), found 503.2.

EXAMPLE 754-{4-[3-(2-{(2R)-2-[(Phenylamino)methyl]pyrrolidinyl}-2-oxoethoxy)phenyl](1,3-thiazol-2-yl)}-5-methylthiothiophene-2-carboxamidineTrifluoroacetate

100 mg (0.093 mmol) of resin-bound2-{3-[2-(5-amidino-2-methylthio-3-thienyl)-1,3-thiazol-4-yl]phenoxy}aceticacid (0.93 mmol/g), as prepared in a manner similar to Example 60, wasreacted with (S)-(+)-2-anilino methyl pyrrolidine (0.5 M, 88 mg) andO-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate) (HATU, 0.5 M, 190 mg), 1-hydroxy-7-azabenzotriazole(HOAt) (0.5M; 68 mg) and diisopropylethylamine (0.233 mmol, 40 μL) in 1mL of anhydrous DMF in a manner similar to Example 63 to afford 13 mg(25% yield) of4-{4-[3-(2-{(2R)-2-[(phenylamino)methyl]pyrrolidinyl}-2-oxoethoxy)phenyl](1,3-thiazol-2-yl)}-5-methylthiothiophene-2-carboxamidinetrifluoroacetate. Mass Spectrum (ESI, m/z) Calcd. for C₂₈H₂₈N₅O₂S₃:563.8 (M+H), found 564.2.

EXAMPLE 76

4-[4-(3-{2-[(3R)-3-(Methoxymetlyl)pyrrolidinyl]-2-oxoethoxy}phenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxamidineTrifluoroacetate

100 mg (0.093 mmol) of resin-bound2-{3-[2-(5-amidino-2-methylthio-3-thienyl)-1,3-thiazol-4-yl]phenoxy}aceticacid (0.93 mmol/g), as prepared in a manner similar to Example 60, wasreacted with (S)-(+)-2-methoxymethyl pyrrolidine (0.5 M, 58 mg) andO-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate) (HATU, 0.5 M, 190 mg), 1-hydroxy-7-azabenzotriazole(HOAt) (0.5M; 68 mg) and diisopropylethylamine (0.233 mmol, 40 μL) in 1mL of anhydrous DMF in a manner similar to Example 63 to afford 16 mg(35% yield) of4-[4-(3-{2-[(3R)-3-(methoxymethyl)pyrrolidinyl]-2-oxoethoxy}phenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxamidinetrifluoroacetate. Mass Spectrum (ESI, m/z) Calcd. for C ₂₃H₂₆N₄O₃S₃:503.2 (M+H), found 503.3.

EXAMPLE 771-(2-{3-[2-(5-Amidino-2-methylthio-3-thienyl)-1,3-thiazol-4-yl]phenoxy}acetyl)piperidine-3-carboxamideTrifluoroacetate

100 mg (0.093 mmol) of resin-bound2-{3-[2-(5-amidino-2-methylthio-3-thienyl)-1,3-thiazol-4-yl]phenoxy}aceticacid (0.93 mmol/g), as prepared in a manner similar to Example 60, wasreacted with nipecotamide (0.5 M, 64 mg) andO-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate) (HATU, 0.5 M, 190 mg), 1-hydroxy-7-azabenzotriazole(HOAt) (0.5M; 68 mg) and diisopropylethylamine (0.233 mmol, 40 μL) in 1mL of anhydrous DMF in a manner similar to Example 63 to afford 11 mg(23% yield)1-(2-{3-[2-(5-amidino-2-methylthio-3-thienyl)-1,3-thiazol-4-yl]phenoxy}acetyl)piperidine-3-carboxamidetrifluoroacetate. Mass Spectrum (ESI, m/z) Calcd. for C₂₃H₂₅N₄O₃S₃:516.2 (M+H), found 516.3.

EXAMPLE 785-Methylthio-4-{4-[3-(trifluoromethoxy)phenyl](1,3-thiazol-2-yl)}thiophene-2-carboxamidineHydrochloride

a) Methyl5-methylthio-4-{4-[3-(trifluoromethoxy)phenyl](1,3-thiazol-2-yl)}thiophene-2-carboxylate:435 mg (1.76 mmol) of methyl4-(aminothioxomethyl)-5-methylthiothiophene-2-carboxylate was dissolvedin 10 mL of reagent grade acetone. 2-bromo-3′-trifluoromethoxyacetophenone, prepared in a manner similar to Example 95, step (a),(1.76 mmol; 497 mg) was added and the solution was allowed to reflux for3 h. The solution was allowed to cool and concentrated to an oil whichwas then dissolved in 150 mL of methylene chloride and washed with 50 mLof 10% HCl (aq.) and 50 mL of 2N NaOH (aq.). The organic layer wasobtained and dried over magnesium sulfate and concentrated affording 877mg (90% yield) of amethyl-5-methylthio-4-{4-[3-(trifluoromethoxy)phenyl](1,3-thiazol-2-yl)}thiophene-2-carboxylate.

b)5-Methylthio-4-{4-[3-(trifluoromethoxy)phenyl](1,3-thiazol-2-yl)}thiophene-2-carboxamidinehydrochloride: To a stirred suspension of 19.4 mmol (1.04 g) of ammoniumchloride (Fisher Scientific) in 20 mL of anhydrous toluene (AldrichChemical Co.) placed under nitrogen atmosphere at 0° C., 9.7 mL (19.4mmol) of 2M trimethylaluminum in toluene (Aldrich Chemical Co.) wasadded via syringe over 15 min and then let stir at 0° C. for 30 minafter which 837 mg (1.94 mmol) ofmethyl-5-methylthio-4-{4-[3-(trifluoromethoxy)phenyl](1,3-thiazol-2-yl)}thiophene-2-carboxylatewas added to solution and allowed to reflux for 3 h. The reactionmixture was quenched by pouring over a slurry of 10 g of silica in 50 mLof chloroform. The silica was poured onto a sintered glass funnel andwashed with ethyl acetate and eluting with a 15% methanol/CH₂C₂ solutionand concentrated. The crude product was purified on 1 mm silica prepplates eluting with 15% methanol/CH₂Cl₂ and treated with 4N HCl/dioxaneto afford 37 mg (5% yield) of5-methylthio-4-{4-[3-(trifluoromethoxy)phenyl](1,3-thiazol-2-yl)}thiophene-2-carboxamidinehydrochloride. ¹H-NMR (DMSO-d₆; 300 MHz) δ 9.43 (bs, 1.9 H), 9.05 (bs,1.9 H), 8.67 (s, 1H), 8.43 (s, 1H), 8.10 (m, 2H), 7.65 (t, 1H), 7.40 (m,1H), 2.8 (s. 3H). Mass Spectrum (LCQ-ESI, m/z) Calcd. for C₁₆H₁₂F₃N₃OS₃:415.5(M+H), found 416.2.

EXAMPLE 795-Methylthio-4-(5-phenyl(1,3-oxazol-2-yl))thiophene-2-carboxamidineHydrochloride

a) Methyl5-methylthio-4-[N-(2-oxo-2-phenylethyl)carbamoyl]thiophene-2-carboxylate:To a stirred suspension of 300 mg (1.29 mmol) of5-(methoxycarbonyl)-2-methylthiothiophene-3-carboxylic acid (as preparedin Example 95) in 10 mL of anhyd CH₂Cl₂ (under a CaSO₄ drying tube) wasadded 135 mL (1.55 mmol) of oxalyl chloride followed by 30 mL of anhydDMF. After stirring for 2 h at room temperature, the mixture wasconcentrated in vacuo. The resulting yellow solid was dissolved in 10 mLof anhyd CH₂Cl₂, cooled (0° C.) and 266 mg (1.55 mmol) of2-aminoacetophenone was added. N,N-diisopropylethylamine (DIEA) (756 mL,4.34 mmol) was added dropwise over 3 min and the mixture stirred for 1 hat room temperature. The mixture was concentrated to an oil andpartitioned between 125 mL of EtOAc and 80 mL of 1 M HCl. The aqueouslayer was extracted with ethyl acetate (2×30 mL) and the combinedorganic phases were washed with 1 M HCl (60 mL), saturated NaHCO₃ (120mL), and brine (120 mL) and dried over Na₂SO₄. After removing thesolvent in vacuo, the residue was recrystallized from MeOH to afford thetitle compound as a cream-colored powder (314 mg, 70%). ¹H-NMR (300 MHz,DMSO-d₆) δ 8.82 (t, 1H, J=6 Hz), 8.43 (s, 1H), 8.02 (d, 2H, J=7 Hz),7.69 (t, 1H, J=7 Hz), 7.57 (t, 2H, J=7 Hz), 4.72 (d, 2H, J=6 Hz), 3.84(s, 3H) and 2.57 (s, 3H). Mass spectrum (MALDI-TOF,a-cyano-4-hydroxycinnamic acid matrix) calcd. for C₁₆H₁₅NO₄S₂: 372.0(M+Na). Found: 372.1.

b) Methyl5-methylthio-4-(5-phenyl(1,3-oxazol-2-yl))thiophene-2-carboxylate: To acooled (0° C.) solution of 80.1 mg (0.229 mmol) of methyl5-methylthio-4-[N-(2-oxo-2-phenylethyl)carbamoyl]thiophene-2-carboxylate(as prepared in the previous step) in 2 mL of anhyd DMF was added 26.7mL (0.286 mmol) of phosphorus oxychloride. After stirring for 20 h atroom temperature, the mixture was concentrated in vacuo. The resultingyellow solid was recrystallized twice from MeOH to afford the titlecompound as a beige powder (48.8 mg, 64%). ¹H-NMR (300 MHz, DMSO-d₆) δ8.26 (s, 1H, 7.88 (s, 1H), 7.86 (d, 2H, J=7 Hz), 7.51 (m, 2H), 7.40 (m,1H), 3.86 (s, 3H), and 2.79 (s, 3H). Mass spectrum (MALDI-TOF,a-cyano-4-hydroxycinnamic acid matrix) calcd. for C₁₆H₁₃NO₃S₂: 332.0(M+H). Found: 331.9.

c) 5-Methylthio-4-(5-phenyl(1,3-oxazol-2-yl))thiophene-2-carboxamidinehydrochloride: Methyl5-methylthio-4-(5-phenyl(1,3-oxazol-2-yl))thiophene-2-carboxylate (37.0mg, 0.112 mmol, as prepared in the previous step) was treated accordingto the procedure in Example 10, step (b) using 59.9 mg (1.12 mmol) ofammonium chloride in 0.50 mL of toluene and 0.560 mL (1.12 mmol) of 2 Mtrimethylaluminum in toluene. The resulting residue was chromatographedon a 5 g silica SPE column (Waters Sep-Pak) with 10% MeOH-CH₂Cl₂ toelute an impurity followed by 20% MeOH-CH₂Cl₂ to give 39 mg of a lightyellow glass. Crystallization from MeOH-MeCN afforded the title compoundas a cream-colored solid (33.4 mg, 85%). ¹H-NMR (300 MHz, DMSO-d₆) δ9.45 (broad s, 2H), 9.13 (broad s, 2H), 8.72 (s, 1H), 7.93 (s, 1H), 7.84(d, 2H, J=7 Hz), 7.53 (t, 2H, J=7 Hz), 7.42 (t, 1H, J=7 Hz), and 2.80(s, 3H). Mass spectrum (MALDI-TOF, a-cyano-4-hydroxycinnamic acidmatrix) calcd. for C₁₅H₁₃N₃OS₂: 316.1 (M+H). Found: 316.5.

EXAMPLES 80 AND 815-Methylthio-4-(4-phenylimidazol-2-yl)thiophene-2-carboxamidinetrifluoroacetate and5-Methylthio-4-[N-(2-oxo-2-phenylethyl)carbamoyl]thiophene-2-carboxamidineTrifluoroacetate

Methyl5-methylthio-4-[N-(2-oxo-2-phenylethyl)carbamoyl]thiophene-2-carboxylate(39.4 mg, 0.100 mmol, as prepared in Example 79, step (a)) was treatedaccording to the procedure in Example 10, step (b) using 64.2 mg (1.20mmol) of ammonium chloride in 0.2 mL of toluene and 0.600 mL (1.20 mmol)of 2 M trimethylaluminum in toluene. The resulting residue waschromatographed on a 5-g silica SPE column (Waters Sep-Pak) with agradient of 5-20% MeOH-CH₂Cl₂ to elute an impurity followed by 20%MeOH-CH₂Cl₂ to give a yellow resin. Crystallization from MeOH-Et₂O-MeCNafforded 16 mg of a yellow solid consisting of two products by ¹H-NMRspectra. A portion of the mixture (11 mg) was purified by reverse-phaseHPLC (5 m C₈ column, 4.6×100 mm, gradient 5-100% solvent B over 15 min,solvent A=0.1% TFA/H₂O, solvent B=0.1% TFA/MeCN, detection at 215 nm) toafford 6 mg of5-methylthio-4-(4-phenylimidazol-2-yl)thiophene-2-carboxamidinetrifluoroacetate as a colorless glass. ¹H-NMR (300 MHz, CD₃OD) δ 8.23(s, 1H), 7.80 (s, 1H), 7.79 (d, 2H, J=7 Hz), 7.48 (m, 2H), 7.39 (m, 1H),and 2.78 (s, 3H). Mass spectrum (electrospray ionization) calcd. forC₁₅H₁₄N₄S₂: 315.1 (M+H). Found: 315.3. Also isolated was 4 mg of5-methylthio-4-[N-(2-oxo-2-phenylethyl)carbamoyl]-thiophene-2-carboxamidinetrifluoroacetate as a colorless glass. ¹H-NMR (300 MHz, DMSO-d₆) δ 9.30(broad s, 2H), 8.86 (broad s, 2H), 8.68 (t, 1H, J=5.4 Hz), 8.43 (s, 1H),8.04 (d, 2H, J=7 Hz), 7.70 (t, 1 H, J=7 Hz), 7.58 (t, 2H, J=7 Hz), 4.78(d, 2H, J=5.4 Hz), and 2.63 (s, 3H). Mass spectrum (electrosprayionization) calcd. for C₁₅H₁₅N₃O₂S₂: 334.1 (M+H). Found: 334.3.

EXAMPLE 82 4-(4-Phenyl-1,3-thiazol-2-yl)thiophene-2-carboxamidineHydrochloride

a) 4-Bromothiophene-2-carboxylic acid: To a cooled (0° C.) solution of10.0 g (47.1 mmol based on 90% purity) of4-bromothiophene-2-carbaldehyde (Aldrich Chemical Company, Milwaukee,Wis.) in 200 mL of t-butanol was added 100 mL of 20% (w/v) NaH₂PO₄followed by 60 mL (0.566 mol) of 2-methyl-2-butene. Sodium chlorite(70.8 mmol based on 80% purity) in 60 mL of water was added withstirring. After stirring the two-phase mixture vigorously for 16 h atroom temperature, the pH of the aqueous layer was adjusted to 1-2 with20% HCl. The layers were separated and the aqueous layer extracted withEtOAc (2×120 mL). The combined organic layers were dried (Na₂SO₄) andconcentrated in vacuo to afford 9.8 g of an off-white solid.Recrystallization from a minimum of MeCN (three crops) gave the titlecompound as a white solid (9.02 g, 93%). ¹H-NMR (300 MHz, CDCl₃) δ 7.79(d, 1H, J=1.5 Hz), and 7.55 (d, 1H, J=1.5 Hz).

b) Methyl 4-bromothiophene-2-carboxylate: To a cooled (−20° C.) solutionof 6.02 g (29.1 mmol) of 4-bromothiophene-2-carboxylic acid (as preparedin the previous step) in 100 mL of anhyd MeOH under nitrogen was added2.55 mL (34.9 mmol) of thionyl chloride dropwise at a rate to keep thetemperature below −5° C. (ca. 8-10 min). After stirring for 1 h at roomtemperature, the mixture was refluxed for 8 h, cooled, and concentratedin vacuo. The resulting 6.7 g of pale amber oil was passed through a 150g pad of silica gel with ca. 600 mL of CH₂Cl₂ (discarding the first 120mL which contained a minor impurity) to afford, after concentration invacuo, the title compound as a colorless oil (6.11 g, 95%). ¹H-NMR (300MHz, CDCl₃) δ 7.69 (d, 1H, J=1.5 Hz), 7.45 (d, 1H, J=1.5 Hz), and 3.90(s, 3H).

c) Methyl 4-cyanothiophene-2-carboxylate: To a solution of 3.82 g (17.3mmol) methyl 4-bromothiophene-2-carboxylate (as prepared in the previousstep) in 10 mL of anhyd DMF was added 3.10 g (34.6 mmol) of copper (1)cyanide. The mixture was heated to reflux with stirring for 18 h, cooledand poured into 100 mL of 10% (w/v) KCN. The mixture was extracted withEtOAc (3×60 mL) and the combined extracts were washed with 150 mL eachof water and brine. The dark solution was dried over Na₂SO₄, treatedwith decolorizing carbon, filtered and the resulting colorless solutionconcentrated in vacuo. The resulting light yellow solid wasrecrystallized from MeOH to afford the title compound as a cream-coloredsolid (1.67 g, 58%). ¹H-NMR (300 MHz, CDCl₃) δ 8.09 (d, 1H, J=1.4 Hz),7.93 (d, 1H, J=1.4 Hz), and 3.93 (s, 3H). IR (film): 2235 and 1712 cm⁻¹.

d) Methyl 4-(aminothioxomethyl)thiophene-2-carboxylate: A solution of1.32 g (7.89 mmol) of methyl 4-cyanothiophene-2-carboxylate (as preparedin the previous step) in 200 mL of reagent grade MeOH was degassed withnitrogen through a fritted gas dispersion tube for 10 min. Triethylamine(5.50 mL, 39.5 mmol) was added and hydrogen sulfide gas was bubbled intothe solution at a vigorous rate for 5 min and then at a minimal rate (asmeasured through an outlet oil bubbler) for 5 h with stirring. The gasintroduction was stopped and the mixture was capped and stirred for 19 hat room temperature. The mixture was concentrated in vacuo to a yellowsolid which was suspended in 10 mL of EtOH, cooled to −20° C., andfiltered washing with 5 mL of cold (−20° C. ) EtOH. The resulting solidwas dried under suction followed by high vacuum to afford the titlecompound as a beige solid (1.31 g, 82%). ¹H-NMR (300 MHz, DMSO-d₆) δ9.85 (broad s, 1H, 9.51 (broad s, 1H, 8.50 (d, 1H, J=1.5 Hz), 8.28 (d,1H, J=1.5 Hz), and 3.84 (s, 3H).

e) Methyl 4-(4-phenyl-1,3-thiazol-2-yl)thiophene-2-carboxylate: To asolution of 150 mg (0.745 mmol) of methyl4-(aminothioxomethyl)-thiophene-2-carboxylate (as prepared in theprevious step) in 6 mL of acetone was added 148 mg (0.745 mmol) of2-bromoacetophenone. After refluxing for 2 h, the mixture wasconcentrated by boiling to a volume of ca. 2 mL. The resulting mixturewas cooled (−10° C. ) and filtered washing with cold acetone (2×0.5 mL).A second crop was obtained from the mother liquors and the combinedcrops dried to afford the title compound as a beige solid (202 mg, 90%).¹H-NMR (300 MHz, DMSO-d₆) δ 8.56 (d, 1H, J=1.5 Hz), 8.25 (d, 1H, J=1.5Hz), 8.18 (s, 1H, 8.04 (d, 2H, J=7 Hz), 7.48 (t, 2H, J=7 Hz), 7.38 (t,1H, J=7 Hz), and 3.89 (s, 3H). Mass spectrum (MALDI-TOF,a-cyano-4-hydroxycinnamic acid matrix) calcd. for C₁₅H₁₁NO₂S₂: 302.0(M+H). Found: 301.8.

f) 4-(4-Phenyl-1,3-thiazol-2-yl)thiophene-2-carboxamidine hydrochloride:Methyl 4-(4-phenyl-13-thiazol-2-yl)thiophene-2-carboxylate (160 mg,0.531 mmol, as prepared in the previous step) was treated according tothe procedure in Example 10, step (b) using 284 mg (5.31 mmol) ofammonium chloride in 2.6 mL of toluene and 2.65 mL (5.30 mmol) of 2 Mtrimethylaluminum in toluene. The resulting light yellow solid waschromatographed on a 10 g silica SPE column (Waters Sep-Pak) with agradient of 5-20% MeOH-CH₂Cl₂. The resulting pale amber glass wastriturated with CH₂Cl₂-MeCN and concentrated in vacuo to afford thetitle compound as a beige solid (68 mg, 45%). ¹H-NMR (300 MHz, DMSO-d₆)δ 9.51 (broad s, 2H), 9.09 (broad s, 2H), 8.71 (d, 1H, J=1.5 Hz), 8.61(d, 1H, J=1.5 Hz), 8.21 (s, 1H, 8.05 (d, 2H, J=7 Hz), 7.50 (t, 2H, J=7Hz), and 7.40 (t, 1H, J=7 Hz). Mass spectrum (MALDI-TOF,a-cyano-4-hydroxycinnamic acid matrix) calcd. for C₁₄H₁₁N₃S₂: 286.0(M+H). Found: 286.3.

EXAMPLE 835-Methylthio-4-[4-benzyl(1,3-thiazol-2-yl)]thiophene-2-carboxamidineHydrochloride

a) Bromo-3-phenylacetone: To a solution of 132 mL (1.00 mmol) ofphenylacetyl chloride in 1.0 mL of anhyd MeCN was added 1.05 mL (2.10mmol) of a 2 M solution of trimethylsilyldiazomethane in hexane. Afterstirring 1 h at room temperature, the mixture was cooled (0° C.) and 300mL (1.50 mmol) of 30 wt % HBr in acetic acid was added dropwise (gasevolution). After stirring 15 min, the mixture was concentrated in vacuoand rapidly chromatographed on a 2 g silica SPE column (Waters Sep-Pak)with 50% CH₂Cl₂-hexane to afford the title compound as a pale yellow oil(201 mg, 94%). ¹H-NMR (300 MHz, CDCl₃) δ 7.2-7.4 (m, 5H), 3.95 (s, 2H),3.92 (s, 2H).

b) Methyl5-methylthio-4-[4-benzyl(1,3-thiazol-²-yl)]thiophene-2-carboxylate:Using a procedure similar to that of Example 10 with 171 mg (0.690 mmol)of methyl 4-(aminothioxomethyl)-5-methylthiothiophene-2-carboxylate (asprepared in Example 82, step (e)) in 4 mL of acetone and 147 mg (0.690mmol) of 1-bromo-3-phenylacetone (as prepared in the previous step)afforded the title compound as a light tan powder (236 mg, 95%). ¹H-NMR(300 MHz, DMSO -d6) δ 8.11 (s, 1H), 7.2-7.4 (m, 5H), 4.11 (s, 2H), 3.84(s, 3H), and 2.72 (s, 3H). Mass spectrum (MALDI-TOF,a-cyano4-hydroxycinnamic acid matrix) calcd. for C₁₇H₁₅NO₂S₃: 362.0(M+H). Found: 362.3.

c) 5-Methylthio-4-[4-benzyl(1,3-thiazol-2-yl)]thiophene-2-carboxamidinehydrochloride: Methyl5-methylthio-4-[4-benzyl(1,3-thiazol-2-yl)]thiophene-2-carboxylate (60mg, 0.166 mmol, as prepared in the previous step) was treated accordingto the procedure in Example 10, step (b) using 88.8 mg (1.66 mmol) ofammonium chloride in 0.5 mL of toluene and 0.830 mL (5.30 mmol) of 2 Mtrimethylaluminum in toluene to afford, after trituration from MeOH withEt₂O, the title compound as a yellow solid (38.2 mg, 60%). ¹H-NMR (300MHz, CD₃OD) δ 8.43 (s, 1H), 7.16-7.33 (m, 5H), 4.15 (s, 2H), and 2.75(s, 3H). Mass spectrum (MALDI-TOF, a-cyano-4-hydroxycinnamic acidmatrix) calcd. for C₁₆H₁₅N₃S₃: 346.0 (M+H). Found: 346.0.

EXAMPLE 84

5-Methylthio-4-(4-phenyl(1,3-oxazol-2-yl))thiophene-2-carboxamidineHydrochloride

a) Methyl4-[N-(2-hydroxy-1-phenylethyl)carbamoyl]-5-methylthiothiophene-2-carboxylate:To a stirred suspension of 1.23 g (5.29 mmol) of5-(methoxycarbonyl)-2-methylthiothiophene-3-carboxylic acid (as preparedin Example 79, step (a)) in 20 mL of anhyd CH₂Cl₂ (under a CaSO₄ dryingtube) was added 1.85 mL (21.2 mmol) of oxalyl chloride followed by 30 mLof anhyd DMF. After stirring for 2 h at room temperature, the mixturewas concentrated in vacuo. The resulting yellow solid was dissolved in20 mL of anhyd CH₂Cl₂, cooled (0° C.) and 1.85 mL ofN,N-diisopropylethylamine (10.6 mmol) and 1.02 g (7.41 mmol) ofphenylglycinol was added and the mixture stirred for 1 h at roomtemperature. The mixture was concentrated to an oil and partitionedbetween 200 mL of EtOAc and 200 mL of saturated NaHCO₃. The organicphase was washed with saturated NaHCO₃ (200 mL), 10% (w/v) citric acid,and brine (200 mL), and dried over Na₂SO₄. After removing the solvent invacuo, the residue was chromatographed on a 10 g silica SPE column(Waters Sep-Pak) with a gradient of 0-20% EtOAc-CH₂Cl₂ to afford thetitle compound as a light yellow solid (1.26 g, 68%). ¹H-NMR (300 MHz,CDCl₃) δ 8.00 (s, 1H), 7.30-7.42 (m, 5H), 7.08 (d, 1H, J=7.2 Hz), 5.26(m, 1H, 3.99 (t, 2H, J=5.4 Hz), 3.89 (s, 3H), 2.60 (s, 3H), and 2.33 (t,1H, J=6.1 Hz). Mass spectrum (electrospray ionization) calcd. forC₁₆H₁₇NO₄S₂: 352.1 (M+H). Found: 352.0.

b) Methyl5-methylthio-4-[N-(2-oxo-1-phenylethyl)carbamoyl]thiophene-2-carboxylate:To a solution of 505 mg (1.44 mmol) methyl4-[N-(2-hydroxy-1-phenylethyl)carbamoyl]-5-methylthiothiophene-2-carboxylate(as prepared in the previous step) in 20 mL of anhydrous CH₂Cl₂ wasadded 856 mg (2.02 mmol) of Dess Martin reagent (Omega Chemical Company,Inc., Levis (Qc) Canada). After stirring in an open flask for 1.5 h atroom temperature, the mixture was concentrated in vacuo. to ca. 10%volume and partitioned between 50 mL of EtOAc and 50 mL of saturatedNaHCO₃-brine (1:1). The organic phase were washed with brine (200 mL),dried over Na₂SO₄ and concentrated in vacuo. Concentrated again fromCH₂Cl₂ followed by high vacuum afforded the title compound as a lightyellow foam (495 mg, 98%) which was used in the next step withoutfurther purification. ¹H-NMR (300 MHz, CDCl₃) δ 9.64 (s, 1H), 8.04 (s,1H), 7.59 (d, 1H, J=5 Hz), 7.36-7.46 (m, 5H), 5.76 (d, 1H, J=5 Hz), 3.90(s, 3H), and 2.62 (s, 3H).

c) Methyl5-methylthio-4-(4-phenyl(1,3-oxazol-2-yl))thiophene-2-carboxylate: To acooled (0° C.) solution of 465 mg (1.33 mmol) methyl5-methylthio-4-[N-(2-oxo-1-phenylethyl)carbamoyl]thiophene-2-carboxylate(as prepared in the previous step) in 6 mL of anhyd DMF was added 186 mL(2.00 mmol) of phosphorus oxychloride. After stirring for 14 h at roomtemperature, the mixture was treated with 10 μL of saturated NaHCO₃ andconcentrated to dryness under high vacuum. The resulting residue waspartitioned between 80 mL of EtOAc and 60 mL of water. The aqueous layerwas extracted with EtOAc (2×10 mL) and the combined organic phaseswashed with brine (60 mL), and dried over Na₂SO₄. The resulting 406 mgof amber-colored solid was recrystallized from CH₂Cl₂-Et₂O to remove themajority of a polar impurity as a cream-colored solid. The remainingmother liquors were chromatographed on a 10 g silica SPE column (WatersSep-Pak) with a gradient of 40-100% CH₂Cl₂-hexane and the resultingresidue triturated with Et₂O-hexane (2:1)) to afford the title compoundas a light beige solid (114 mg, 26%). ¹H-NMR (300 MHz, CDCl₃) δ 8.24 (s,1H, 7.93 (s, 1H), 7.83 (m, 2H), 7.43 (m, 2H1), 7.33 (m, 1H), 3.91 (s,3H), and 2.72 (s, 3H). Mass spectrum (ESI) calcd. for C₁₆H₁₃NO₃S₂: 332.0(M+H). Found: 332.2.

d) 5-Methylthio-4-(4-phenyl(1,3-oxazol-2-yl))thiophene-2-carboxamidinehydrochloride: Methyl5-methylthio-4-(4-phenyl(1,3-oxazol-2-yl))thiophene-2-carboxylate (80.3mg, 0.242 mmol, as prepared in the previous step) was treated accordingto the procedure in Example 10, step (b) using 155 mg (2.90 mmol) ofammonium chloride in 1.45 mL of toluene and 1.45 mL (2.90 mmol) of 2 Mtrimethylaluminum in toluene. The resulting light yellow solid waschromatographed on a 5 g silica SPE column (Waters Sep-Pak) with 10%MeOH-CH₂Cl₂ to give a light yellow resin. Crystallization from MeOH-Et₂O(ca. 1:3) afforded the title compound as a yellow solid (62.2 mg, 82%).¹H-NMR (300 MHz, DMSO-d₆) δ 9.39 (broad s, 2H), 8.97 (broad s, 2H), 8.78(s, 1H), 8.60 (s, 1H), 7.89 (d, 2H, J=7 Hz), 7.49 (t, 2H, J=7 Hz), 7.38(t, 1H, J=7 Hz), and 2.80 (s, 3H). Mass spectrum (ESI) calcd. forC₁₅H₁₃N₃OS₂: 316.1 (M+H). Found: 316.2.

EXAMPLE 854-[4-(4-Hydroxy-3-methoxyphenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxamidineHydrochloride

a) 4-(Chlorocarbonyl)-2-methoxyphenyl acetate: To a stirred suspensionof 1.00 g (4.76 mmol) of 4-acetoxy-3-methoxybenzoic acid (Pfaltz andBauer, Inc.) in 4 mL of anhyd CH₂Cl₂ (under a CaSO₄ drying tube) wasadded 4.15 mL (47.6 mmol) of oxalyl chloride followed by 25 mL of anhydDMF. After stirring for 4 h at room temperature, the mixture wasconcentrated in vacuo to afford the title compound as light yellowcrystals (1.12 g, 103%). ¹H-NMR (300 MHz, CDCl₃) δ 7.81 (dd, 1H, J=8.4,2.1 Hz), 7.66 (d, 1H, 2.1 Hz), 7.19 (d, 1H, 8.4 Hz), 3.91 (s, 3H), and2.35 (s, 3H).

b) 4-(2-Bromoacetyl)-2-methoxyphenyl acetate: To a solution of 1.09 g(4.6 mmol) of 4-(chlorocarbonyl)-2-methoxyphenyl acetate (as prepared inthe precious step) in 10 mL of anhyd CH₂Cl₂ was added 10.0 mL (20.0mmol) of a 2 M solution of trimethylsilyldiazomethane in hexane. Afterstirring 2 h at room temperature, the mixture was cooled (0° C. ) and3.20 mL (16.0 mmol) of 30 wt % HBr in acetic acid was added dropwise(gas evolution). After stirring 5 min, the mixture was concentrated invacuo and rapidly chromatographed on a 10-g silica SPE column (WatersSep-Pak) with CH₂Cl₂ to afford the title compound as a light yellowcrystalline solid (1.28 g, 97%). ¹H-NMR (300 MHz, CDCl₃) δ 7.63 (d, 1H,1.9 Hz), 7.59 (dd, 1H, J=8.2, 1.9 Hz), 7.16 (d, 1H, 8.2 Hz), 4.43 (s,2H), 3.91 (s, 3H), and 2.35 (s, 3H).

c)2-Methoxy-4-{2-[5-(methoxycarbonyl)-2-methylthio(3-thienyl)](1,3-thiazol-4-yl}phenylacetate: Using a procedure similar to that of Example 82, step (e) with1.00 g (4.04 mmol) of methyl4-(aminothioxomethyl)-5-methylthiothiophene-2-carboxylate (MaybridgeChemical Company, Cornwall, UK) in 15 mL of reagent acetone and 1.16 g(4.04 mmol) of 4-(2-bromoacetyl)-2-methoxyphenyl acetate (as prepared inthe previous step) afforded the title compound as 1.42 g of a yellowsolid which, according to the ¹H-NMR spectrum, consisted of a ca. 1:1mixture of the title compound and the corresponding compound resultingfrom partial loss of the acetate. ¹H-NMR (300 MHz, DMSO-d₆) δ 8.27 (s,1H, 8.22 (s, 1H, 8.19 (s, 1H), 8.00 (s, 1H), 7.78 (d, 1H, 1.9 Hz), 7.67(dd, 1H, J=8.2, 1.9 Hz), 7.61 (d, 1H, 1.9Hz), 7.51 (dd, 1H, J=8.2, 1.9Hz), 7.19 (d, 1H, 8.2 Hz), 6.86 (d, 1H, 8.2 Hz), 8.87 (m, 12H), 2.76 (s,3H), 2.75 (s, 3H), and 2.28 (s, 3H). Mass spectrum (ESI) calcd. forC₁₉H₁₇NO₃S₃ and C₁₇H₁₅NO₃S₃ 436.0 (M+H) and 394.1 (M+H). Found: 436.1and 394.2. The mixture was used without further purification in thefollowing step where formation of the amidine involves concomitantremoval of the acetate.

d)4-[4-(4-hydroxy-3-methoxyphenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxamidinehydrochloride: A portion of the mixture (500 mg, ca. 1.21 mmol as basedon the ¹H-NMR integration) containing the2-methoxy-4-{2-[5-(methoxycarbonyl)-2-methylthio(3-thienyl)](1,3-thiazol-4-yl)}phenylacetate (as prepared in the previous step) was treated according to theprocedure in Example 10, step (b) using 610 mg (11.4 mmol) of ammoniumchloride in 5.7 mL of toluene and 5.70 mL (11.4 mmol) of 2 Mtrimethylaluminum in toluene. After chromatography of the resultingresidue on a 10 g silica SPE column (Waters Sep-30 Pak) with a gradientof 5-20% MeOH-CH₂Cl₂ to obtain a yellow glass which was recrystallizedfrom MeOH-CH₂Cl₂ to afford the title compound as a pale yellow solid 192mg, 42%). ¹H-NMR (300 MHz, DMSO-d₆) δ 9.35 (broad s, 2H), 9.27 (s, 1H),8.97 (broad s, 2H), 8.62 (s, 1H), 8.04 (s, 1H), 7.62 (s, 1H), 7.54 (d,1H J=8.2 Hz), 6.88 (d, 1H, J=8.2 Hz), 3.87 (s, 3H), and 2.79 (s, 3H).Mass spectrum (ESI) calcd. for C₁₆H₁₅N₃O₂S₃: 378.0(M+H). Found: 378.1.

EXAMPLE 864-[4-(3-Hydroxy-4-methoxyphenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxamidinehydrochloride

a) 3-Acetyloxy-4-methoxybenzoic acid: To a suspension of 600 mg (3.57mmol) of 3-hydroxy-4-methoxybenzoic acid (Aldrich Chemical Company,Milwaukee, Wis.) in 5 mL of anhyd CH₂Cl₂ was added 1.31 mL (7.50 mmol)of N,N-diisopropylethylamine and the mixture stirred until homogeneous(ca. 5 min). Acetyl chloride (305 mL, 4.28 mmol) was added dropwise over2 min followed by 2.0 mg ((0.016 mmol) of 4-dimethylaminopyridine. Afterstirring at room temperature for 1 h, the mixture was poured into 50 mLof EtOAc and washed with 1 M HCl (3×25 mL). The organic phase wasextracted with saturated NaHCO₃ (6×15 mL) and the combined extractssaturated with solid NaCl and acidified to pH 2 with conc HCl. Theresulting suspension was extracted with EtOAc (3×20 mL) and the combinedextracts were dried over Na₂SO₄ and concentrated in vacuo to afford thetitle compound as a light beige powder (463 mg, 62%). ¹H-NMR (300 MHz,CDCl₃) δ 8.00 (dd, 1H, J=8.7, 2.0 Hz), 7.79 (d, 1H, 2.0 Hz), 7.00 (d,1H, 8.7 Hz), 3.91 (s, 3H), and 2.34 (s, 3H).

b) 3-(Chlorocarbonyl)-6-methoxyphenyl acetate: Using the procedure inExample 85 step (a), 400 mg (1.90 mmol) of 3-acetyloxy-4-methoxybenzoicacid (as prepared in the previous step) was treated with 663 mL (7.60mmol) of oxalyl chloride and 25 mL of anhyd DMF for 2 h to afford, afterworkup, the title compound as a beige crystalline solid which was usedin the following step without further purification.

c) 5-(2-Bromoacetyl)-2-methoxyphenyl acetate: Using the procedure inExample 85, step (b), the entire sample of3-(chlorocarbonyl)-6-methoxyphenyl acetate (as prepared in the previousstep) in 5 mL of anhyd CH₂Cl₂ was treated with 2.09 mL (4.18 mmol) of a2 M solution of trimethylsilyldiazomethane in hexane and 456 mL (2.28mmol) of 30 wt % HBr in acetic acid. Chromatography as in Example 85,step (b) followed by recrystallization from CH₂Cl₂-hexane afforded thetitle compound as a faintly yellow solid (366 mg, 67%). ¹H-NMR (300 MHz,CDCl₃) δ 7.79 (dd, 1H, J=8.6, 2.2 Hz), 7.70 (d, 1H, 2.2 Hz), 7.03 (d,1H, 8.6 Hz), 4.38 (s, 2H), 3.92 (s, 3H), and 2.34 (s, 3H).

d)2-Methoxy-5-{2-[5-(methoxycarbonyl)-2-methylthio(3-thienyl)](1,3-thiazol-4-yl)}phenylacetate: Using a procedure similar to that of Example 82, step (e) with282 mg (1.14 mmol) of methyl4-(aminothioxomethyl)-5-methylthiothiophene-2-carboxylate (MaybridgeChemical Company, Cornwall, UK) in 4 mL of acetone and 3.27 mg (1.14mmol) of 5-(2-bromoacetyl)-2-methoxyphenyl acetate (as prepared in theprevious step) afforded a yellow solid (374 mg) which, according to the¹H-NMR spectrum, consisted of a 3:7 mixture of the title compound andthe corresponding compound resulting from partial loss of the acetate.Mass spectrum (ESI) calcd. for C₁₉H₁₇NO₅S₃ and C₁₇H₁₅NO₃S₃ 436.0 (M+H)and 394.1 (M+H). Found: 436.0 and 394.0. The mixture was used withoutfurther purification in the following step where formation of theamidine involves concomitant removal of the acetate.

e)4-[4-(3-Hydroxy-4-methoxyphenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxamidinehydrochiloride: A portion of the mixture (320 mg, ca. 0.788 mmol asbased on the ¹H-NMR spectrum) containing the2-methoxy-5-{2-[5-(methoxvcarbonyl)-2-methylthio(3-thienyl)](1,3-thiazol-4-yl)}phenylacetate (as prepared in the previous step) was treated according to theprocedure in Example 10, step (b), using 415 mg (7.76 mmol) of ammoniumchloride in 3.5 mL of toluene and 3.88 mL (7.66 mmol) of 2 Mtrimethylaluminum in toluene. After chromatography of the resultingresidue on a 10 g silica SPE column (Waters Sep-Pak) with 10-40%MeOH-CH₂Cl₂, a light yellow solid was obtained which was dissolved in 45mL of DMF and filtered to remove silica gel. Concentration under highvacuum and recrystallization from MeOH—Et₂O afforded the title compoundas a light tan solid (132 mg, 44%). ¹H-NMR (300 MHz, DMSO-d₆) δ 9.49(broad s, 2H), 9.16 (broad s, 2H), 8.67 (s, 1H), 7.98 (s, 1H), 7.5(obscured m, 3H), 7.00 (obscured d, 1H, J=8.3 Hz), 3.82 (s, 3H), and2.79 (s, 3H). Mass spectrum (ESI) calcd. for C₁₆H₁₅N₃O₂S₃: 378.0 (M+H).Found: 378.1.

EXAMPLE 87 5-Metlythlio-4-(N-phenylcarbamoyl)thiophene-2-carboxamidinehydrochloride

a) Methyl 5-methylthio-4-(N-phenylcarbamoyl)thiophene-2-carboxylate: To182 mg (0.785 mmol) of5-(methoxycarbonyl)-2-methylthiothiophene-3-carboxylic acid (as preparedin Example 95) in 4 mL of anhyd CH₂Cl₂ was treated with 275 mL (3.15mmol) of oxalyl chloride and 6 mL of anhyd DMF for 2 h similar toExample 79, step (a); followed by 206 mL (1.18 mmol) ofN,N-diisopropylethylamine and 85.9 mL (0.942 =mol) of aniline in 3 mL ofanhyd CH₂Cl₂ for 20 min. The mixture was poured into 25 mL of EtOAc andwashed with 1 M HCl (2×25 mL), saturated NaHCO₃ (2×25 mL), and brine (25mL), and dried over Na₂SO₄. Removal of the solvent in vacuo, affordedthe pure title compound as a light yellow solid (163 mg, 68%). ¹H-NMR(300 MHz, CDCl₃) δ 8.23 (broad s, 1H), 8.10 (s, 1H), 7.63 (d, 2H, J=7Hz), 7.36 (t, 2H, J=7 Hz), 7.15 (t, 2H, J=7 Hz), 3.90 (s, 3H), and 2.64(s, 3H).

b) 5-Methylthio-4-(N-phenylcarbamoyl)thiophzene-2-carboxamidinehydrochloride: Methyl5-methylthio-4-(N-phenylcarbamoyl)thiophene-2-carboxylate (60.0 mg, 0.195 mmol, as prepared in the previous step) was treated similarly to theprocedure in Example 10, step (b) using 310 mg (5.80 mmol) of ammoniumchloride in 2 mL of toluene and 2.90 mL (5.80 mmol) of 2 Mtrimethylaluminum in toluene for 6 h. Chromatography of the resultingresidue on a 2 g silica SPE column (Waters Sep-Pak) with a gradient of5-20% MeOH—CH₂Cl₂, followed by crystallization from MeOH-Et₂O affordedthe title compound as a beige solid (40.3 mg, 71%). ¹H-NMR (300 MHz,DMSO-d₆) δ 10.24 (s, 1H), 9.34 (broad s, 2H), 9.05 (broad s, 2H), 8.75(s, 1H), 7.73 (d, 2H, J=8 Hz), 7.36 (t, 2H, J=8 Hz), 7.11 (m, 1H), and2.67 (s, 3H). Mass spectrum (ESI) calcd. for C₁₃H₁₃N₃OS₂: 292.1 (M+H).Found: 292.4.

EXAMPLE 88 AND 895-Methylthio-4-[N-benzylcarbamoyl]thiophene-2-carboxamidinehydrochllorideand 4-{Imino[benzylamino]methyl}-5-methylthiothiophene-2-carboxamidinehydrochloride

a) Methyl 5-methylthio-4-[N-benzylcarbamoyl]thiophene-2-carboxylate: Theidentical procedure of Example 87, step (a) was used with 103 mL (0.942mmol) of benzylamine and the same amounts of all other reagents toafford the title compound as a light yellow solid (167 mg, 66%). ¹H-NMR(300 MHz, CDCl₃) δ 7.93 (s, 1H), 7.28-7.38 (m, 5H), 6.58 (broad s, 1H),4.62 (s, 2H, J=5.7 Hz), 3.87 (s, 3H), and 2.60 (s, 3H).

b)5-Methylthio-4-[N-benzylcarbamoyl]thiophene-2-carboxamidinehydrochlorideand4-{Imino[benzylamino]methyl}-5-methylthiothiophene-2-carboxamidinelzydrochloride:Methyl 5-methylthio-4-[N-benzylcarbamoyl]thiophene-2-carboxylate (62.7mg, 0.195 mmol, as prepared in the previous step) was treated similarlyto the procedure in Example 10, step (b) using 310 mg (5.80 mmol) ofammonium chloride in 2 mL of toluene and 2.90 mL (5.80 mmol) of 2 Mtrimethylaluminum in toluene for 6 h.

Chromatography of the resulting residue on a 2 g silica SPE columnn(Waters Sep-Pak) with a gradient of 5-20% MeOH—CH₂Cl₂, followed bycrystallization from MeOH—Et₂O afforded5-methylthio-4-[N-benzylcarbamoyl]thiophene-2-carboxamidinehydrochlorideas a beige solid (21.1 mg, 35%). ¹H-NMR (300 MHz, DMSO-d₆) δ 7.93 (s,1H), 7.28-7.38 (m, 5H), 6.58 (broad s, 1H), 4.62 (s, 2H, J=5.7 Hz), 3.87(s, 3H), and 2.60 (s, 3H). Mass spectrum (ESI) calcd. for C₁₄H₁₅N₃OS₂:306.1 (M+H). Found: 306.6.

Also isolated and crystallized from MeOH—Et₂O was the more polar4-{imino[benzylamino]methyl}-5-methylthiothiophene-2-carboxamidinehydrochlorideas a beige solid (32.0 mg, 54%). ¹N-NMR (300 MHz, DMSO-d₆) consistentwith desired product as broad mixture of rotomers. Mass spectrum (ESI)calcd. for C₁₄H₁₆N₄S₂: 305.1 (M+H). Found: 305.8.

EXAMPLE 90 AND 914-[N-Metlyl-N-benzylcarbamoyl]-5-methylthiothiophene-2-carboxamidinehydrochloride and4-{Imino[methylbenzylamino]methyl}-5-methylthiothiophene-2-carboxamidinehydrochloride

a) Methyl4-[N-methyl-N-benzylcarbamoyl]-5-methylthiothiophene-2-carboxylate: Theidentical procedure of Example 87, step (a) was used with 122 mL (0.942mmol) of N-benzylmethylamine and the same amounts of all other reagentsto afford the title compound as a light yellow solid (169 mg, 64%).¹H-NMR (300 MHz, CDCl₃) δ 7.68 (s, 1H), 7.34 (m, 5H), 4.6 (broad m, 2H),3.86 (s, 3H), 2.91 (m, 3H), and 2.60 (s, 3H).

b) 4-[N-Methyl-N-benzylcarbamoyl]-5-methylthiothiophene-2-carboxamidinehydrochloride and4-{Imino[methylbenzylaminol]methyl}-5-methylthiothiophene-2-carboxamidinehydrochloride: Methyl4-[N-methyl-N-benzylcarbamoyl]-5-methylthiothiophene-2-carboxylate (65.4mg, 0.195 mmol, as prepared in the previous step) was treated similarlyto the procedure in Example 10, step (a) using 310 mg (5.80 mmol) ofammonium chloride in 2 mL of toluene and 2.90 mL (5.80 mmol) of 2 Mtrimethylaluminum in toluene for 6 h.

Chromatography of the resulting residue on a 2 g silica SPE column(Waters Sep-Pak) with a gradient of 5-20% MeOH—CH₂Cl₂ afforded4-[N-methyl-N-benzylcarbamoyl]-5-methylthiothiophene-2-carboxamidinehydrochloride as a amber-colored glass (34.3 mg, 55%). ¹H-NMR (300 MHz,DMSO-d₆) δ 9.32 (broad s, 2H), 9.06 (broad s, 2H), 8.11 (s, 1H), 7.36(m, 5H), 4.66 (m, 2H), 2.88 (s, 3H) and 2.66 (s, 3H). Mass spectrum(ESI) calcd. for C₁₅H₁₇N³OS₂: 320.1 (M+H). Found: 320.4.

Also isolated and then crystallized from MeOH—Et₂O was the more polar4-{imino[methylbenzylamino]methyl}-5-methylthiothiophene-2-carboxamidinehydrochloride as a beige solid (19.8 mg, 32%). ¹H-NMR (300 MHz, DMSO-d₆)consistent with desired product as broad mixture of rotomers. Massspectrum (ESI) calcd. for C₁₅H₁₈N₄S₂: 319.1 (M+H). Found: 319.6.

EXAMPLE 92 AND 935-Methylthio-4-[N-(2-phenylethyl)carbamoyl]thiophene-2-carboxamidinehydrochloride and4-{Imino[(2-phenylethyl)amino]methyl}-5-methylthiothiophene-2-carboxamidinehydrochloride

a) Methyl5-methtylthio-4-[N-(2-phenylethyl)carbamoyl]thiophene-2-carboxylate: Theidentical procedure of Example 87, step (a) was used with 118 mL (0.942mmol) of phenethylamine and the same amounts of all other reagents toafford the title compound as a light yellow solid (165 mg, 63%). ¹H-NMR(300 MHz, CDCl₃) δ 7.86 (s, 1H), 7.30-7.35 (m, 5H), 6.44 (m, 1H), 3.87(s, 3H), 3.70 (q, 2H, J=7 Hz), 2.93 (t, 2H, J=7 Hz), and 2.53 (s, 3H).

b) 5-Methlylthio-4-[N-(2-phenyletlyl)carbamoyl]thiophene-2-carboxamidinehydrochloride and4-{Imino[(2-phenylethlyl)amino]methyl}-5-methylthiothiophene-2-carboxamidinehydrochloride: Methyl5-methylthio-4-[N-(2-phenylethyl)carbamoyl]thiophene-2-carboxylate (65.4mg, 0.195 mmol, as prepared in the previous step) was treated similarlyto the procedure in Example 10, step (a) using 310 mg (5.80 mmol) ofammonium chloride in 2 mL of toluene and 2.90 mL (5.80 mmol) of 2 Mtrimethylaluminum in toluene for 6 h.

Chromatography of the resulting residue on a 2 g silica SPE column(Waters Sep-Pak) with a gradient of 5-20% MeOH—CH₂Cl₂, followed bycrystallization from MeOH—Et₂O afforded5-methylthio-4-[N-(2-phenyiethyl)carbamoyl]thiophene-2-carboxanidinehydrochloride as a beige solid (17.4 mg, 28%). ¹H-NMR (300 MHz, DMSO-d₆)δ 8.8-9.3 (broad m, 4H), 8.48 (m, 1H), 8.35 (s, 1H), 7.26 (m, 5H), 3.44(m, 2H), 2.82 (t, 3H, J=7.5 Hz), and 2.61 (s, 3H). Mass spectrunm (ESI)calcd. for C₁₅H₁₇N₃OS₂: 320.1 (M+H). Found: 320.4.

Also isolated and crystallized from MeOH—Et₂O was the more polar4-{imino[(2-phenylethyl)amino]methyl}-5-methylthiothiophene-2-carboxamidinehydrochloride as a beige solid (19.1 mg, 31%). ¹H-NMR (300 MHz, DMSO-d₆)δ 8.37 (s, 1H), 7.2-7.4 (m, 5H), 3.70 (t, 2H, J=7.6 Hz), 2.96 (t, 2H.J=7.6 Hz), and 2.71 (s, 3H). Mass spectrum (ESI) calcd. for C₁₅H₁₈N₄S₂:319.1 (M+H). Found: 319.5.

EXAMPLE 943-Amino-2-aza-3-[5-methylthio-4-(4-phenyl(1,3-thiazol-2-yl))(2-thienyl)]prop-2-enenitrile

To 100 mg (0.302 mnmol) of5-methylthio-4-(4-phenyl(1,3-thiazol-2-yl))thiophene-2-carboxarnidine(as prepared in Example 10, step b) in 3 mL of EtOH was added 29.6 mg(0.604 mmol) of cyanamide as a solution in 0.3 mL of water. The mixturewas heated to reflux and 0.302 mL (0.302 mmol) of 1 M aqueous KOH wasadded. After 3 h, the mixture was cooled (0° C.) and filtered washingwith ice-cold EtOH. The resulting solid was dried in vacuo to afford thetitle compound as a light yellow powder (78.4 mg, 73%). ¹H-NMR (300 MHz,DMSO-d₆) δ 9.31 (broad s, 1H), 8.70 (broad s, 1H), 8.63 (s, 1H), 8.19(s, 1H), 8.09 (d, 2H, J=7 Hz), 7.49 (t, 2H, J=7 Hz), 7.39 (t, 1H, J=7Hz), and 2.75 (s, 3H). Mass spectrum (MALDI-TOF,a-cyano-4-hydroxycinnamic acid matrix) calcd. for C₁₆H₁₂N₄S₃: 357.0(M+H). Found: 357.1.

EXAMPLE 95 5-(Methoxycarbonyl)-2-methylthaiothiophene-3-carboxylic acid

Methyl 4-cyano-5-methylthiothiophene-2-carboxylate (2.20 g, 10.3 mmol,Maybridge Chemical Company, Cornwall, UK) and tetrafluorophthalic acid(2.45 g, 10.3 mmol) in an 8-mL sealable pressure tube (Ace GlassCompany) with stir bar was heated to 160° C. The molten mixture wasstirred for 4 days, cooled and the resulting residue broken up andextracted by refluxing with 80 mL chloroform. The mixture was cooled,decolorizing carbon (ca. 0.5 g) was added and the mixture filtered(Celite). The resulting solution was extracted with saturated NaHCO₃(4×30 mL) and the combined aqueous extracts acidified to pH 1-2 withconc HCl and filtered to provide a light tan solid. After dissolving thesolid in a minimum of 1 M K₂CO₃ (35-40 mL) and filtering (washing with10-20 mL of water) to clarify the solution, it was slowly acidified topH 6.5-7.0 with stirring and filtered (Celite) to remove a brownprecipitate. The pH adjustment and filtration was repeated and theresulting solution was saturated with solid NaCl and acidified to pH 1-2with conc HCl. The precipitate was filtered, washed with water (3×10 mL)and dried over P₂O₅ under high vacuum to afford the title compound as acream-colored powder (1.24 g, 52%). ¹H-NMR 300 MHz, DMSO-d₆) δ 13.14(broad s, 1H), 7.89 (s, 1H), 3.82 (s, 3H) and 2.64 (s, 3H). Massspectrum (ESI, negative mode) calcd. for C₈H₈O₄S₂: 232.0 (M−). Found:231.7.

EXAMPLE 965-Ethylthio-4-(4-phenyl(1,3-thiazol-2-yl))thiophene-2-carboxamidinehydrochloride 5

a) Methyl4-(4-phenyl(1,3-thiazol-2-yl))-5-(methtylsulfonyl)thiophene-2-carboxylate:Using the procedure of Example 141, step (a) with 600 mg (1.73 mmol) ofmethyl5-methylthio-4-(4-phenyl(1,3-thiazol-2-yl))thiophene-2-carboxylate asprepared in Example 10, step (a) afforded 642 mg (98%) of the titlecompound as a light yellow powder. ¹H-NMR (300 MHz, CDCl₃) δ 7.93 (s,1H), 7.90 (m, 2H), 7.63 (s, 1H), 7.47 (m, 2H), 7.39 (m, 1H), 3.98 (s,3H) and 3.73 (s, 3H). Mass spectrum (ESI, m/z): calcd. for C₁₆H₁₃NO₄S₃380.0 (M+H), found 380.2.

b) 4-(4-Phenyl)(1,3-thiazol-2-yl))-5-(methylsulfonyl)thiophene-2-carboxatridinehydrochloride: Using the procedure of Example 141, step (b) with 560 mg(1.48 mmol) methyl4-[4-(4-chlorophenyl)(1,3-thiazol-2-yl)]-5-(methylsulfonyl)thiophene-2-carboxylateas prepared in the previous step afforded 392 mg (66%) of the titlecompound as a off-white solid. ¹H-NMR (300 MHz, DMSO-d₆) δ 9.7 (broad s,2H), 9.4 (broad s, 2H), 8.58 (s, 1H), 8.43 (s, 1H), 8.02 (d, 2H, J=7Hz), 7.52 (t, 2H, J=7 Hz), 7.43 (t, 1H, J=7 Hz), and 3.90 (s, 31H). Massspectrum (ESI, m/z): calcd. for C₁₅H₁₃N₃O₂S₃ 364.0 (M+H), found 364.1.

c) 5-Ethylthio-4-(4-phenyl(1,3-thiazol-2-yl))thiophene-2-carboxamidinehydrochloride: Using the procedure of Example 141, step (c) with 23.1 mg(0.0578 mmol) of the4-(4-phenyl)(1,3-thiazol-2-yl))-5-(methylsulfonyl)thiophene-2-carboxamidinehydrochloride (as prepared in the previous step), 64.1 mL(0.867 mmol) ofethanethiol (in 2 portions over 2 h) and 40.3 mL (0.231 mmol) of DIEA in3 mL of methanol gave a yellow resin which was chromatographed on a 2 gsilica SPE column (Waters Sep-Pak) with a gradient of 0-15% MeOH—CH₂Cl₂,followed by trituration with CH₂Cl₂ to afford the title compound as anoff-white solid (21.7 mg, 98%). ¹H-NMR (300 MHz, DMSO-d₆) δ 9.45 (broads, 2H), 9.07 (broad s, 2H), 8.68 (s, 1H), 8.28 (s, 1H), 8.09 (d, 2H, J=7Hz), 7.51 (t, 2H, J=7 Hz), 7.40 (t, 1H, J=7 Hz), 3.23 (q, 2H, J=7 Hz)and 1.42 (t, 3H, J=7 Hz). Mass spectrum (ESI) calcd. for C₁₆H₁₅N₃S₃:346.1 (M+H). Found: 346.2.

EXAMPLE 975-Methylthio-4-[4-(phenoxymethyl)(1,3-thiazol-2-yl)]thiophene-2-carboxamidinehydrochloride

a) 3-Bromo-1-phenoxyacetone: To a solution of 6.c (0.050 mmol) ofphenoxyacetyl chloride in 250 mL of anhyd MeCN in a 1-dram short vial(Wheaton Glass) was added 50 mL (0.100 mmol) of a 2 M solution oftrimethylsilyldiazomethane in hexane and the vial capped with aPTFE-lined cap. After stirring 1 h at room temperature on a vortexshaker, the mixture was cooled (0° C.) and 21 mL (0.105 mmol) of 30 wt %HBr in acetic acid was added dropwise (gas evolution). After vortexingfor 10 min, the mixture was concentrated in vacuo on a vacuum centrifugeconcentrator (Speed-Vac, Savant Instruments, Inc.) to provide anamber-colored oil which was used directly in the following step.

b) Methyl5-metliylthio-4-[4-(henoxymethyl)(1,3-thiazol-2-yl)]thiophene-2-carboxylate:To the 3-bromo-1-phenoxyacetone (as prepared in the previous step in a1-dram vial) was added 14.8 mg (0.060 mmol) of methyl4-(aminothioxomethyl)-5-methylthiothiophene-2-carboxylate (MaybridgeChemical Company, Cornwall, UK) as 1.48 mL of a 10 mg /mL solution inacetone. The vial was tightly capped and placed on a heated platformshaker (Innova model 4080, New Brunswick Scientific Co., Inc.) andvortexed at 55° C. and 250 rpm for 4 h. To the resulting mixture wasadded 50 mg (0.150 mmol) of diethylaminomethyl-polystyrene resin (FlukaChemika-Biochemika, 3.0 mmol/g) as 0.50 mL of a 100 mg/mL suspension inacetone and the mixture vortexed briefly. Chloroacetylpolystyrene resin(30 mg, 0.150 mmol, Advanced ChemTech Inc., 5.0 mmol/g) was then addedfollowed by (0.750 mg, 0.005 mmol) Nal as 100 mL of a 7.5 mg/mL solutionin acetone. The mixture was again capped tightly and placed on a heatedplatforim shaker and vortexed at 55° C. and 250 rpm for 22 h. Themixture was filtered through a 2 mL fritted column (BioRad Biospinminicolumn) washing with acetone (2×0.5 mL) and MeOH (2×0.5 mL) into a 2dram vial and concentrated on a vacuum centrifuge concentrator to afford21.0 mg of the title compound as an off-white solid. ¹H-NMR (300 MHz,DMSO-d₆) δ 8.17 (s, 1H), 7.82 (s, 1H), 7.13 (m, 2H), 7.07 (m, 2H), 6.96(m, 1H), 5.22 (s, 2H), 3.85 (s, 3H), and 2.74 (s, 3H). Mass spectrum(MALDI-TOF, a-cyano-4-hydroxycianamic acid matrix) calcd. forC₁₇H₁₅NO₃S₃: 378.0 (M+H). Found: 378.3.

c)5-Methylthio-4-[4-(phenoxymethyl)(1,3-thiazol-2-yl)]thiophene-2-carboxamidinehydrochloride: The methyl5-methylthio-4-[4-(phenoxymethyl)(1,3-thiazol-2-yl)]thiophene-2-carboxylate(as prepared in the previous step)under nitrogen in a 2 dram vial with amicro magnetic stir bar) was capped with an open-top phenolic capcontaining a PTFE-backed silicone septum. A 1 M solution of the reagentfreshly prepared from trimethylaluminum and ammonium chloride in tolueneaccording to the procedure in Example 10, step b (0.750 mL, 0.750 mmol)was added by syringe by puncturing the septum once with the needle toallow venting of gas followed by a second puncture to inject thereagent. The vial was placed in an aluminum heating block under nitrogen(Fisher Scientific Dry Bath Incubator fitted with a custom-made nitrogenmanifold cover). The manifold was flushed with nitrogen and the reactionstirred by means of a large magnetic stir motor placed inverted on topof the manifold. The reaction was heated to 100 ° C. for 4 h, and cooledto room temperature over ca. 2 h. The contents of the vial were quenchedcarefully into 0.5 g of silica gel in 2 mL of CH₂Cl₂, capped and shakento homogeneity. The slurry was filtered through a 4-mL fritted column(Isolab microcolumin) into a 2-dram vial washing with CH₂Cl₂ (2×1 mL),CH₂Cl₂-MeOH (1:1, 1×1 mL) and MeOH(2×1 mL) and the filtrate concentratedon a vacuum centrifuge concentrator to a yellow solid. Filtrationthrough a 500 mg silica SPE column (Supelco LC-Si) with 10% MeOH —CH₂Cl₂afforded the title compound as a yellow solid (14.8 mg). ¹H-NMR (300MHz. DMSO-d₆) δ 9.45 (d, 2H, J=8.2 Hz), 9.11 (d, 2H, J=8.2 Hz), 8.97(broad s, 2H), 8.65 (s, 1H), 7.90 (s, 1H), 7.0-7.5 (m, 5H), 5.25 (s,2H), and 2.79 (s, 3H). Mass spectrum (MALDI-TOF, gentisic acid matrix)calcd. for C₁₇H₁₅NO₃S₃: 362.0 (M+H). Found: 361.7.

EXAMPLES 98-126

Examples 98-104 were carried out using the procedure of Example 97,steps using 0.050 mmol of the reagent specified in the table. Examples105-126 were carried out using the procedure of Example 97, steps (a),(b) and (c) using 0.05 mmol of reagent.

Mass Spectrum (ESI) Example Reagent Compound Formula Calcd (M + H) Found 98 1-bromopinacolone 4-[4-(tert-butyl)(1,3-thiazol-2-yl)]-5-methylthio-C13 H17 N3 S3 312.1 312.2 thiophene-2-carboxamidine hydrochloride  994-fluorophenacyl bromide4-[4-(4-fluorophenyl)(1,3-thiazol-2-yl)]-5-methyl- C15 H12 F N3 S3 350.0350.2 thiothiophene-2-carboxamidine hydrochloride 100 4-cyanophenacylbromide 4-[4-(4-amidinophenyl)(1,3-thiazol-2-yl)]-5- C16 H15 N5 S3 374.1374.2 methylthiothiophene-2-carboxamidine hydrochloride 1013-fluorophenacyl bromide4-[4-(3-fluorophenyl)(1,3-thiazol-2-yl)]-5-methyl- C15 H12 F N3 S3 350.0350.2 thiothiophene-2-carboxamidine hydrochloride 1024-(diethylamino)phenacyl bromide4-{4-[4-(diethylamino)phenyl](1,3-thiazol-2-yl)}- C19 H22 N4 S3 403.1403.2 5-methylthiothiophene-2-carboxamidine hydrochloride 1033-chlorophenacyl bromide4-[4-(3-chlorophenyl)(1,3-thiazol-2-yl)]-5-methyl- C15 H12 C1 N3 S3366.0 366.1 thiothiophene-2-carboxamidine hydrochloride 1043,4-difluorophenacyl bromide4-[4-(3,4-difluorophenyl)(1,3-thiazol-2-yl)]-5- C15 H11 F2 N3 S3 368.0368.2 methylthiothiophene-2-carboxamidine hydrochloride 1052,6-difluorobenzoyl chloride4-[4-(2,6-difluorophenyl)(1,3-thiazol-2-yl)]-5- C15 H11 F2 N3 S3 368.0368.2 methylthiothiophene-2-carboxamidine hydrochloride 1064-ethoxybenzoyl chloride 4-[4-(4-ethoxyphenyl)(1,3-thiazol-2-yl)]-5- C17H17 N3 O S3 376.1 376.2 methylthiothiophene-2-carboxamidinehydrochloride 107 4-chlorophenoxyacetyl chloride4-{4-[(4-chlorophenoxy)methyl](1,3-thiazol-2- C16 H14 C1 N3 O S3 396.0396.1 yl)}-5-methylthiothiophene-2-carboxamidine hydrochloride 108cyclopentanecarbonyl chloride4-(4-cyclopentyl(1,3-thiazol-2-yl))-5-methylthio- C14 H17 N3 S3 324.1324.2 thiophene-2-carboxamidine hydrochloride 109 1-naphthoyl chloride5-methylthio-4-(4-naphthyl(1,3-thiazol-2-yl))- C19 H15 N3 S3 382.1 382.2thiophene-2-carboxamidine hydrochloride 110 3,5-dichlorobenzoyl chloride4-[4-(3,5-dichlorophenyl)(1,3-thiazol-2-yl)]-5- C15 H11 C12 N3 S3 400.0400.1 methylthiothiophene-2-carboxamidine hydrochloride 1112,5-difluorobenzoyl chloride4-[4-(2,5-difluorophenyl)(1,3-thiazol-2-yl)]-5- C15 H11 F2 N3 S3 368.0368.2 methylthiothiophene-2-carboxamidine hydrochloride 1129-fluorenone-4-carbonyl chloride5-methylthio-4-[4-(9-oxofluoren-4-yl)(1,3-thiazol- C22 H15 N3 O S3 434.1434.2 2-yl)]thiophene-2-carboxamidine hydrochloride 1133-methoxyphenylacetyl chloride4-{4-[(3-methoxyphenyl)methyl](1,3-thiazol-2- C17 H17 N3 O S3 376.1376.2 yl)}-5-methylthiothiophene-2-carboxamidine hydrochloride 1144-methyl valeroyl chloride4-[4-(3-methylbutyl)(1,3-thiazol-2-yl)]-5-methyl- C14 H19 N3 S3 326.1326.2 thiothiophene-2-carboxamidine hydrochloride 1153-(2-chlorophenyl)-5-methyl-4-{4-[3-(2-chlorophenyl)-5-methylisoxazol-4-yl]- C19 H15 C1 N4 O S3447.0 447.1 isoxazole-4-carbonyl chloride(1,3-thiazol-2-yl)}-5-methylthiothiophene-2- carboxamidine hydrochloride116 4-n-amyloxybenzoyl chloride5-methylthio-4-[4-(4-pentyloxyphenyl)(1,3- C20 H23 N3 O S3 418.1 418.2thiazol-2-yl)]thiophene-2-carboxamidine hydro- chloride 1171-(4-chlorophenyl)-1-cyclo-4-{4-[(4-chlorophenyl)cyclopentyl](1,3-thiazol-2- C20 H20 C1 N3 S3 434.1434.3 pentanecarbonyl-chlorideyl)}-5-methylthiothiophene-2-carboxamidine hydrochloride 1184-(trifluoromethoxy)- 5-methylthio-4-{4-[4-(trifluoromethoxy)phenyl]-C16 H12 F3 N3 O S3 416.0 416.1 benzoyl chloride(1,3-thiazol-2-yl)}thiophene-2-carboxamidine hydrochloride 1193-chlorobenzo[b]thiophene-4-[4-(3-chlorobenzo[b]thiophen-2-yl)(1,3-thiazol- C17 H12 C1 N3 S4 422.0422.1 2-carbonyl chloride 2-yl)]-5-methylthiothiophene-2-carboxamidinehydrochloride 120 3-(2-chloro-6-fluorophenyl)-5-4-{4-[3-(6-chloro-2-fluorophenyl)-5-methyl- C19 H14 C1 F N4 O S3 465.0465.1 methylisoxazole-4-carbonylisoxazol-4-yl](1,3-thiazol-2-yl)}-5-methylthio- chloridethiophene-2-carboxamidine hydrochloride 121 3-cyanobenzoyl chloride4-[4-(3-amidinophenyl)(1,3-thiazol-2-yl)]-5- C16 H15 N5 S3 374.1 374.7methylthiothiophene-2-carboxamidine hydro- chloride 1224-methoxyphenylacetyl chloride4-{4-[(4-methoxyphenyl)methyl](1,3-thiazol-2- C17 H17 N3 O S3 376.1376.2 yl)}-5-methylthiothiophene-2-carboxamidine hydrochloride 1233-(t-butyl)-1-benzylpyrazole-5- 4-{4-(3-(tert-butyl)pyrazol-5-yl](1,3-C16 H19 N5 S3 378.1 378.2 carbonyl chloridethiazol-2-yl)}-5-methylthiothiophene-2-carbo- xamidine hydrochloride 1243-(4-chlorophenyl)-2,2- 5-methylthio-4-[4-(1-methylvinyl)(1,3-thiazol-2-C12 H13 N3 S3 296.0 296.2 dimethylpropanoyl chlorideyl)]thiophene-2-carboxamidine hydrochloride 125n-(1-naphthalenesulfonyl)-1-5-methylthio-4-(4-{1-[(naphthylsulfonyl)amino]- C27 H24 N4 O2 S4 565.1565.1 phenylalanyl chloride2-phenylethyl}(1,3-thiazol-2-yl))thiophene-2- carboxamidinehydrochloride 126 2-bromo-5-methoxybenzoyl4-[4-(2-bromo-5-methoxyphenyl)(1,3-thiazol-2- C16 H14 Br N3 O S3 440.0440.2 chloride yl)]-5-methylthiothiophene-2-carboxamidine hydrochloride

EXAMPLE 127

a) 1-[3,5-Bis(trifluoromethyl)phenyl]-2-bromoethan-1-one: A stirredsuspension of 1 g (3.9 nimol) of 3,5-bis(trifluoromethyl)acetophenone(Lancaster, Windham, N.H., USA) in dry methanol (20 mL) and 1 g (15mmol, 2.6 eq) of poly(4-vinyl pyridinium tribromide) (Aldrich,Milwaukee, Wis., USA) was protected from moisture with dry nitrogen, andheated at reflux for 70 min. The pol)ymer was filtered from the cooledsolution and washed with methanol and twice with dichloromethane. Thesolvents were removed in vacuo to give1-[3,5-bis(trifluoromethy)phenyl]-2-bromoethan-1-one (1.2 g, 92%).¹H-NMR (DMSO-d₆; 300 MHz) δ 8.43 (m, 2H), 8.12 (m, 1H), 4.46 (s, 3H).

b) Methyl4-{4-[3,5-bis(trifluoromethyl)phenyl](1,3-thiazol-2-yl)}-5-methylthiothiophene-2-carboxylate:A solution of 75 mg (0.3 mmol) of methyl4-(aminothioxomethyl)-5-methylthiothiophene-2-carboxylate (Maybridge,Cornwall, UK) was reacted with 101 mg (0.3 mmol) of1-[3,5-bis(trifluoromethyl)phenyl]-2-5 bromoethane-1-one in a mannersimilar Example 8, step (a) to give methyl4-{4-[3,5-bis(trifluoromethyl)phenyl](1,3-thiazol-2-yl)}-5-methylthiothiophene-2-carboxylate(7 mg, 5%) as a solid. ¹H-NMR (DMSO-d₆; 300 MHz) δ 8.75 (s, 1H), 8.73(m, 2H), 8.29 (s, 1H), 8.13 (m, 1H), 3.87 (s, 3H), 2.79 (s, 3H). Massspectrum (MALDI-TOF, CHCA matrix, m/z): Calcd. for C₁₈H₁₁NO₂S₃F₆, 484.0(M+H), found 484.0.

c)4-{4-[3,5-Bis(trifluoromethyl)phenyl](1,3-thiazol-2-yl)-5-methylithiothiophene-2-carboxamidine:Methyl4-[4-3,5-bis(trifluoromethyl)phenyl](1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxylate(7 mg, 14.5 mmol) was treated in a manner similar to that for Example10, step (b), to give4-{4-[3,5-bis(trifluoromethyl)phenyl](1,3-thiazol-2-yl)}-5-methylthiothiophene-2-carboxamidine (6 mg, 89%) as a yellow solid.¹H-NMR (DMSO-d₆; 300 MHz) 8.78 (s, 1H), 8.74 (s, 2H), 8.62 (s, 1H), 8.15(s, 1 H), 2.82 (s, 3H). Mass spectrum (MALDI-TOF, CHCA matrix, m/z):Calcd. for C₁₇H₁₁N₃S₃F₆, 468.0 (M+H), found 468.0.

EXAMPLE 128

a) 2-Bromo-1-[3-fluoro-5-(trifluorometltyl)phenyl]ethan-1-one: A stirredsuspension of 1 g (4.5 mmol) of 3-fluoro-5-(trifluoromethyl)acetophenone(Lancaster, Windham, N.H., USA) was treated in a manner similar to thatfor Example 127, step (a) to give of a 1:1 mixture of2-bromo-1-[3-fluoro-5-(trifluoromethyl)phenyl]ethan-1-one anddibrominated product (1.6 g, 100%). ¹H-NMR (DMSO-d₆; 300 MHz) δ8.25-7.52 (m, 6H), 6.54 (s, 1H), 4.42 (s, 2H).

b) Methyl4-{4-[3-fluoro-5-(trifluoromethyl)phenyl](1,3-thiazol-2-yl)}-5-methylthiothiophene-2-carboxylate:A solution of 75 mg (0.3 mmol) of methyl4-(aminothioxomethyl)-5-methylthiothiophene-2-carboxylate (Maybridge.Cornwall, UK) was reacted with of 86 mg (0.3 mmol)2-bromo-1-[3-fluoro-5-(trifluoromethyl)phenyl]ethan-1-one in a mannersimilar to Example 8, step (a) to give, methyl4-{4-[3-fluoro-5-(trifluoromethyl)phenyl](1,3-thiazol-2-yl)}-5-methylthiothiophene-2-carboxylate (41 mg, 31%) as a solid. ¹H-NMR(DMSO-d₆; 300 MHz) δ 8.59 (s, 1H), 8.29 (m, 1H), 8.27 (s, 1H), 8.25 and8.21 (m, 1H, 1:1 ratio conformers), 7.73 and 7.70 (m, 1H, 1:1 ratioconformers). Mass spectrum (MALDI-TOF, CHCA matrix, m/z): Calcd. forC₁₇H₁₁NO₂S₃F₄, 434.0 (M+H), found 434.0.

c)4-{4-[3-Fluoro-5-(trifluoromethyl)phenyl](1,3-thiazol-2-yl)}-5-methylthiothiophene-2-carboxamidine:Methyl4-{4-[3-fluoro-5-(trifluoromethyl)phenyl](1,3-thiazol-2-yl)}-5-methylthiothiophene-2-carboxylate(40 mg, 0.92 mmol) was treated in a manner similar to that for Example10, step (b), to give4-{4-[3-fluoro-5-(trifluoromethyl)phehyl](1,3-thiazol-2-yl)-5-methylthiothiophene-2-carboxamidine(31 mg, 81%) as a yellow solid. ¹H-NMR (DMSO-d₆; 300 MHz) δ 9.36 (br s,2H), 9.01 (br s, 2H), 8.68 (s, 1H), 8.63 (s, 1H), 8.30 (m, 1H), 8.25 and8.22 (m, 1H, 1:1 ratio conformers), 7.75 and 7.73 (m, 1H, 1:1 ratioconformers), 2.82 (s, 3H). Mass spectrum (MALDI-TOF, CHCA matrix, m/z):Calcd. for C₁₆H₁₁N₃S₃F₄, 418.5 (M+H), found 418.0.

EXAMPLE 129

a) 2-Bromo-1-[3-fluoro-5-(trifluoromethyl)phenyl]propan-1-one: A stirredsuspension of 1 g (4.5 mmol) of1-[3-fluoro-5-(trifluoromethyl)phenyl]propan-1-one (Lancaster, Windham,N.H., USA) was treated in a manner similar to that for Example 127, step(a) to give 2-bromo-1-[3-fluoro-5-(trifluoromethyl)phenyl]propan-1-one(1.33 g, 99%). ¹H-NMR (DMSO-d₆; 300 MHz) δ 8.07 (m, 1H), 7.92 and 7.89(m, 1H, 1:1 ratio conformers), 7.57 and 7.55 (m, 1H, 1:1 ratioconformers), 5.20 (q, 1H, J=6.6 Hz), 1.93 (d, 3H, J=6.6 Hz).

b) Methyl4-{4-[3-fluoro-5-(trifluoromethyl)phenyl]-5-methyl(1,3-thiazol-2-yl)}-5-methylthiothiophene-2-carboxylate:A solution of 75 mg (0.3 mmol) of methyl4-(aminothioxomethyl)-5-methylthiothiophene-2-carboxylate (Maybridge,Cornwall, UK) was reacted with 90 mg (0.3 mmol) of2-bromo-1-[3-fluoro-5-(trifluoromethyl)phenyl]propan-1-one in a mannersimilar to Example 8, step (a) to give, methyl4-{4-[3-fluoro-5-(trifluoromethyl)phenyl]-5-mnethyl(1,3-thiazol-2-yl)}-5-methylthiothiophene-2-carboxylate(31.9 mg, 24%) as a solid. ¹H-NMR (DMSO-d₆; 300 MHz) δ 8.17 (s, 1H),7.98 (m, 1H), 7.95 and 7.92 (m, 1H. 1:1 ratio conformers), 7.77 and 7.74(m, 1H, 1:1 ratio conformers), 3.87 (s, 3H), 2.75 (s, 3H), 2.70 (s, 3H).Mass spectrum (MALDI-TOF, CHCA matrix, m/z): Calcd. for C₁₈H₁₃NO₂S₃F₄,448.0 (M+H), found 448.0.

c)4-}4-[3-Fluoro-5-(trifluorometihyl)phenyl]-5-methyl(1,3-thiazol-2-yl)5-methylthiothiopliene-2-carboxamidine:Methyl4-{4-[3-fluoro-5-(trifluoromethyl)phenyl]-5-methyl(1,3-thiazol-2-yl)}-5-methylthiothiophene-2-carboxylate(30 mg, 0.067 mmol) was treated in a manner similar to that for Example10, step (b), to give4-{4-[3-fluoro-5-(trifluoromethyl)phenyl]-5-methyl(1,3-thiazol-2-yl)}-5-methylthiothiophene-2-carboxamidine(32 mg, quantitive yield) as a yellow solid. ¹H-NMR (DMSO-d₆; 300 MHz) δ9.42 (br s, 2H), 9.03 (br s, 2H), 8.60 (s, 1H), 7.98 (m, 1H), 7.95 and7.92 (m, 1H, 1:1 ratio conformers), 7.79 and 7.76 (m, 1H, 1:1 ratioconformers), 2.78 (s, 3H), 2.71 (s, 3H). Mass spectrum (MALDI-TOF, CHCAmatrix, m/z): Calcd. for C₁₇H₁₃N₃S₃F₄, 432.0 (M+H), found 432.6.

EXAMPLE 130

a) 1-[3,5-Bis(trifluoromethyl)phenyl]-2-bromopropan-1-one: A stirredsuspension of 1 g (3.7 mmol) of1-[3,5-bis(trifluoromethyl)phenyl]-propan-1-one (Lancaster, Windham,N.J., USA) treated in a manner similar to that for Example 127, step (a)to give 2-bromo-1-[3-fluoro-5-(trifluoromethyl)phenyl]propan-1-one (1.1g, 86%). ¹H-NMR (DMSO-d₆; 300 MHz) δ 8.46 (m, 2H), 8.09 (m, 1), 5.26 (q,1H, J=6.6Hz), 1.96 (d, 3H, J=6.5 Hz). Mass spectrum (MALDI-TOF, CHCAmatrix, mtz): Calcd. for C₁₁H₇OBrF₆, 349.0 (M+H), found 348.9.

b) Methyl4-{4-[3,5-bis(trifluoromethyl)phenyl]-5-methyl(1,3-thiazol-2-yl)}-5-methylthiothiophene-2-carboxylate:A solution of 75 mg (0.3 mmol) of methyl4-(aminothioxomethyl)-5-methylthiothiophene-2-carboxylate (Maybridge,Cornwall, UK) was reacted with 105 mg1-[3,5-Bis(trifluoromethyl)phenyl]-2-bromopropan-1-one in a mannersimilar to Example 8, step (a) to give, after preparative thin-layerchromatrography purification, methyl4-{4-[3,5-bis(trifluoromethyl)phenyl]-5-methyl(1,3-thiazol-2-yl)}5-methylthiothiophene-2-carboxylate(16.2 mg, 11%) as a solid. ¹H-NMR (DMSO-d₆; 300 MHz) δ 8.41 (m, 2H),8.18 (m, 2H), 3.86 (s, 3H), 2.75 (s, 3H), 2.71 (s, 3H). Mass spectrum(MALDI-TOF, CHCA matrix, m/z): Calcd. for C₁₉H₁₃NO₂S₃F₆, 498.0 (M+H),found 497.6.

c)4-{4-[3,5-Bis(trifluoromethyl)phenyl]-5-methyl(1,3thiazol-2-yl)}-5-methylthiothiophene-2-carboxamidine:Methyl4-{4-[3,5-bis(trifluoromethyl)phenyl]-5-methyl(1,3-thiazol-2-yl)}-5-methylthiothiophene-2-carboxylate(15 mg, 0.031 mmol) was treated in a manner similar to that for Example10, step (b), to give4-{4-[3,5-bis(trifluoromethyl)phenyl]-5-methyl(1,3-thiazol-2-yl)}-5-methylthiothiophene-2-carboxamidine(13 mg, 88%) as a yellow solid. ¹H-NMR (DMSO-d₆; 300 MHz) δ 9.39 (br s,2H), 8.94 (br s, 2H), 8.58 (s, 1H), 8.40 (m, 2H), 8.19 (m, 1H), 2.79 (s,3H), 2.73 (s, 3H). Mass spectrum (MALDI-TOF, CHCA matrix, m/z): Calcd.for C₁₈H₁₃N₃S₃F₆, 482.0 (M+H), found 482.5.

EXAMPLE 131

a) 2-Bromo-1,2-diphenylethan-1-one: A stirred suspension of 0.2 g (1mmol) of deoxybenzoin was treated in a manner similar to that forExample 127, step (a) to give 2-bromo-1,2-diphenylethan-1-one (270 mg,98%). ¹H-NMR (DMSO-d₆; 300 MHz) δ 8.10-8.06 (m, 2H), 7.95-7.31 (m, 8H),7.21 (s, 1H).

b) Methlyl4-(4,5-diphenyl(1,3-thiazol-2-yl))-5-methtytltiothiophene-2-carboxylate:A solution of 75 mg (0.3 mnmol) of methyl4-(aminothioxomethyl)-5-methylthiothiophene-2-carboxylate (Maybridge,Cornwall, UK) was reacted with 92 mg, 0.3 mmol) of2-bromo-1,2-diphenylethan-1-one in a manner similar to Example 8, step(a) to give, after preparative thin-layer chromatrography purification,methyl4-(4,5-diphenyl(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxylate(9 mg, 7%) as a solid. ¹H-NMR (DMSO-d₆; 300 MHz) δ 8.94 (br s, 0.4H),8.66 (s, 1H), 8.60 (br s, 0.3 H), 8.08 (s, 1H), 7.93 and 7.20 (ABquartet, 2H,J=8.7 Hz), 7.68 and 7.35 (AB quartet, 2H, J=8.2 Hz), 2.77(s, 3H), ), 2.33 (s, 3H). Mass spectrum (MALDI-TOF, CHCA matrix, m/z):Calcd. for C₂₂H₁₇NO₂S₃, 424.0 (M+H), found 424.3.

c)4-(4,5-Diphenyl(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxamidine:Methyl4-(4,5-diphenyl(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxylate(9 mg, 0.021 mmol) was treated in a manner similar to that for Example10, step (b), to give4-(4,5-diphenyl(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxamidine(3 mg, 35%) as a brown oil. Mass spectrum (MALDI-TOF, CHCA matrix, m/z):Calcd. for C₂₁,H₁₇N₃S₃, 408.1 (M+H), found 408.0.

EXAMPLE 132

a) Methyl4-(4-benzo[b]thiophen-2-yl(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxylate:A solution of 75 mg (0.3 mmol) of methyl4-(aminothioxomethyl)-5-methylthiothiophene-2-carboxylate was reactedwith 77 mg (0.3 nimol) of 3-bromoacetylbenzo[b]thiophene (Maybridge,Cornwall, UK) in a manner similar to Example 8, step (a) to give, afterpreparative thin-layer chromatrography purification, methyl4-(4-benzo[b]thiophen-2-yl(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxylate(28 mg, 23%) as a solid. ¹H-NMR (DMSO-d₆; 300 MHz) δ 8.63 (d, 1H, J=7.4Hz), 8.30 (s, 1H), 8.25 (s, 1H), 8.22 (s, 1H), 7.53-7.46 (m, 2H), 3.87(s, 3H), 2.78 (s, 3H).

b)4-(4-Benzo[b]thiophen-2-yl(1,3-thiazol-22-yl))-5-methylthiothiophene-2-carboxamidine:Methyl4-(4-benzo[b]thiophen-2-yl(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxylate(28 mg, 0.69 mmol) was treated in a manner similar to that for Example10, step (b), to give4-(4-benzo[b]thiophen-2-yl(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxamidine(17 mg, 64%) as a brown solid. ¹H-NMR (DMSO-d₆; 300 MHz) δ 9.22 (br s,4H), 8.68 (s, 1H), 8.66 (d, 1H,

J=7.6 Hz), 8.30 (s, 1H), 8.25 (s, 1H), 8.10 (d, 1H,J=7.3 Hz), 7.55-7.45(m, 2H), 2.81 (s, 3H). Mass spectrum (MALDI-TOF, GA matrix, m/z): Calcd.for C₁₇H₁₃N₃S₄, 388.0 (M+H), found 388.2.

EXAMPLE 133

a) Methyl4-(4-benzo[d]benzo[3,4-bifuran-3-yl(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxylate:A solution of 75 mg (0.3 mmol) of methyl4-(aminothioxomethyl)-5-methylthiothiophene-2-carboxylate (Maybridge,Cornwall, UK) was reacted with 86 mg (0.3 mmol) of2-(bromoacetyl)-dibenzofuran (Aldrich, Milwaukee, Wis., USA) in a mannersimilar to Example 8, step (a) to give, after preparative thin-layerchromatrography purification, methyl4-(4,5-diphenyl(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxylate(45 mg, 36%) as a solid. ¹H-NMR (DMSO-d₆; 300 MHz) δ 8.83-7.44 (m, 71H),8.29 (s, 1H), 8.27 (s, 1H), 3.88 (s, 31H), 2.80 (s, 3H). Mass spectrum(MALDI-TOF, CHCA matrix, m/z): Calcd. for C₂₂H₁₅NO₃S₃, 438.0 (M+H),found 438.5.

b)4-4-Benzo[d]benzo[3,4-b]furan-3-yl(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxamidine:Methyl4-(4-benzo[d]benzo[3,4-b]furan-3-yl(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxylate(45 mg, 0.11 mmol) was treated in a manner similar to that for Example10, step (b), to give 4-4-benzo[d]benzo[3,4-b]furan-3-yl(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxamidine(16.8 mg, 36%) as a yellow solid. ¹H-NMR (DMSO-d₆; 300 MHz) δ 9.72-9.10(m, 3H), 8.84-7.31 (m, 9H), 2.84 (s, 3H). Mass spectrum (MALDI-TOF, CHCAmatrix, m/z): Calcd. for C₂₁,H₁₅N₃OS₃, 422.0 (M+H), found 421.9.

EXAMPLE 134

a) Methlyl4-(4-(4-nitrophenyl)(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxylate:A solution of 1 g (4 mmol) of methyl4-(aminothioxomethyl)-5-methylthiothiophene-2-carboxylate (Maybridge,Cornwall, UK) was reacted with 987 mg (4 mmol) of2-bromo-4′-nitroacetophenone in a manner similar to Example 8, step (a)to give methyl4-(4-(4-nitrophenyl)(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxylate(1.7 g, quantitive yield) as a brown solid. ¹H-NMR (DMSO-d₆; 300 MHz) δ8.57 (s, 1H), 8.34 (s, 4H), 8.25 (s, 1H), 3.94 (s, 3H), 3.81 (s, 3H).Mass spectrum (MALDI-TOF, CHCA matrix, m/z): Calcd. for C₁₆H₁₂N₂O₄S₃393.0 (M+H), found 392.8.

b) Methyl4-(4-(4-aminophenyl)(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxylate:Methyl4-(4-(4-nitrophenyl)(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxylate(800 mg, 2 mmol) was dissolved in 150 mL tetrahydrofuran and treatedwith 20% titanium chloride solution (Fisher Scientific, Pittsburgh, Pa.,USA) for 1 h. The mixture was poured into 2 M sodium hydroxide solution(100 mL), extracted with dichloromethane (4×50 mL). The combined organiclayers were washed with saturated brine solution and dried overanhydrous sodium sulfate. The solid was filtered off, and the solventremoved in vacuo. This material was purified by column chromatography onsilica gel (30 g) eluting with dichloromethane:methanol 98/2 (v:v) togive methyl4-(4-(4-aminophenyl)(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxylate(500 mg, 69%) as a solid. ¹H-NMR (DMSO-d₆; 300 MHz) δ 8.17 (s, 1H), 7.77(s, 1H), 7.74 and 6.62 (AB quartet, 2H, J=8.6 Hz), 5.35 (s, 2H), 3.86(s, 3H), 2.74 (s, 3H)) Mass spectrum (MALDI-TOF, CHCA matrix, m/z):Calcd. for C₁₆H₁₄N₂O₂S₃ 363.0 (M+H), found 362.4.

c) Methyl4-(4-{4-[(methylsulfonyl)amino]phenyl}(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxylate:Methyl4-(4-(4-aminophenyl)(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxylate(200 mg, 0.55 mmol) was dissolved in dry dichloromethane (20 mL). Tothis, N-methyl morpholine (150 μL, 1.3 8 mmol) and dimethylaminopyridine(6.1 mg, 0.055 mmol) were added, the mixture was cooled on an ice bath,and methanesulfonyl chloride (43 μL, 0.55 mmol) was added dropwise. Themixture was then stirred for 6 hdays at room temperature. The mixturewas partitioned between saturated sodium bicarbonate (50 mL) anddichloromethane (20 mL). The aqueous layer was extracted withdichloromethane (3×20 mL), and the combined organic layers were washedwith saturated sodium bicarbonate (20 mL), brine (2×20 mL), and driedover anhydrous sodium sulfate. The solvent was removed in vacuo. Columnchromatrography on silica gel (100 g) eluting withdichloromethane:methanol 99/1 (v:v), gave methyl4-(4-{4-[(methylsulfonyl)aminolphenyl}(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxylate (155 mg, 64%)as a solid. ¹H-NMR (DMSO-d₆; 300 MHz) δ 9.92 (s, 1H), 8.22 (s, 1H), 8.11(s, 1H), 8.40 and 6.90 (AB quartet, 2H, J=8.7 Hz), 3.87 (s, 3H), 3.05(s, 3H), 2.76 (s, 3H). Mass spectrum (MALDI-TOF, CHCA matrix m/z):Calcd. for C₁₇H₁₆N₂O₄S₄ 441.0 (M+H), found 441.2.

d)4-(4-{4-[(Methylsulfonyl)amino]phenyl}(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxamidine:Methyl 4-(4-{4-[(methylsulfonyl)amino]phenyl}(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxylate (81 mg, 0.184mmol) was treated in a manner similar to that for Example 10, step (b),to give4-(4-{4-[(methylsulfonyl)amino]phenyl}(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxamidine(24.9 mg, 32%) as a light browvn solid. ¹H-NMR (DMSO-d₆; 300 MHz) δ 10.0(br s, 1H), 9.3 (br s, 2H), 8.98 (s. 1H), 8.65 (s, 1H), 8.21 (s, 1H),7.98 and 7.5 (AB quartet, 2H, J=8.6 Hz), 3.05 (s, 3H), 2.79 (s, 3H).Mass spectrum (MALDI-TOF, CHCA matrix, m/z): Calcd. for C₁₆H₁₆N₄O₂S₄425.0 (M+H), found 425.1.

EXAMPLE 135

a) Methyl4-(4-(4-[(phenysulfonyl)amino]phenyl(1,3-thiazol-2-yl))-5-methiothiothiophene-2-carboxylate:Methyl4-(4-(4-aminophenyl)(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxylate(100 mg, 0.28 inmol) was dissolved in dry dichloromethane (10 mL). Tothis, N-methyl morpholine (46 μL, 0.42 mmol) and dimethylaminopyridine(3.4 mg, 0.028 mmol) were added, the mixture was cooled on an ice bath,and benzenesulfonyl chloride 35 μL, 0.28 mmol) was added dropwise. Themixture was then stirred for 24 h at room temperature. Workup wascarried out as in Example 134, step (c). Trituration withdichloromethane and methanol gave methyl4-(4-{4-[(phenylsulfonyl)amino]phenyl}(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxylate(44 mg, 31%) as a crystalline solid. ¹H-NMR (DMSO-d₆; 300 MHz) δ 10.46(s, 1H), 8.19 (s, 1H), 8.05 (s, 1H), 7.91 and 7.19 (AB quartet, 2H,J=8.7 Hz), 7.81 (m, 2H), 7.64-7.54 (m, 3H) 3.85 (s, 3H), 2.74 (s, 3H).Mass spectrum (MALDI-TOF, CHCA matrix, m/z): Calcd. for C₂₂H₁₈N₂O₄S₄504.2 (M+H), found 504.1

b)4-(4-{4-[(Phenylsulfonyl)amino]phenyl}(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxamidine:Methyl4-(4-{4-[(phenylsulfonyl)aninolphenyl}(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxylate(30 mg, 0.060 mmol) was treated in a manner similar to that for Example10, step (b), to give4-(4-{4-[(phenylsulfonyl)amino]phenyl}(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxamidine(12.6 mg, 43%) as a yellow solid. ¹H-NMR (DMSO-d₆; 300 MHz) δ 9.13 (brs, 3H), 8.60 (s, 1H), 8.08 (s. 1H) 7.93 and 7.20 (AB quartet, 2H, J=8.7Hz), 7.82-7.79 (m, 2H), 7.65-7.53 (m, 3H) 3.85 (s, 3H), 2.74 (s, 3H).Mass spectrum (MALDI-TOF, CHCA matrix, m/z): Calcd. for C₂₁H₁₈N₄O₂S₄,87.0 (M+H), found 487.7.

EXAMPLE 136

a) Methyl4-(4-{4-[(trifluoromethylsulfonyl)amino]phenyl}(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxylate:Methyl4-(4-(4-aminophenyl)(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxylate(200 mg, 0.55 mmol) was dissolved in dry pyridine (20 mL). The mixturewas cooled on an ice bath, and trifluoromethanesulfonic anhydride (0.5mL, 3 mmol) was added. The mixture was then stirred for 1.5 h at roomtemperature. Workup was carried out as in Example 134, step (c). Columnchromatrography on silica gel (30 g) eluting with hexanes:ethyl acetate7/3 (v:v), followed by preparative thin layer chromatography elutingwith dichloromethane:methanol 99/1 (v:v) gave methyl4-(4-{4-[(trifluoromethylsulfonyl)amino]phenyl}(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxylate(160 mg, 59%) as a solid. ¹H-NMR (DMSO-d₆; 300 MHz) δ 8.48 and 7.87(s,3/2 ratio conformers, 1H), 8.23 (s, 1H), 8.21 (s, 1H). 8.29 and 7.84 (ABquartet, 2H, 2/3 ratio conformers, J=8.7 Hz), 8.10 and 7.37 (AB quartet,2H, J=8.7 Hz), 3.87 and 3.86 (s, 2/3 ratio conformers, 3H), 2.77 and2.76 (s, 2/3 ratio conformers, 3H). Mass spectrum (MALDI-TOF, CHCAmatrix, m/z): Calcd. for C₁₇H₁₃N₂O₄S₄F₄ 495.0 (M+H), found 495.6

b)4-(4-{4-[(Trifluoromethylsulfonyl)amino]phenyl}(1,3-thiazol-2-yl))-5-methylthiothioplhene-2-carboxamidine:Methyl4-(4-{4-[(trifluoromethylsulfonyl)amino]phenyl}(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxylate(30 mg, 0.061 mmol) was treated in a manner similar to that for Example10, step (b), to give of4-(4-{4-[(trifluoromethylsulfonyl)amino]phenyl}(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxamidine(21.6 mg, 74%) as a light brown solid. ¹H-NMR (DMSO-d₆; 300 MHz) δ 9.39(br s, 2H), 8.97 (br s. 2H), 8.64 (s, 1H), 8.24 (s, 1H), 8.12 and 7.39(AB quartet, 2H, J=8.7 Hz), 4.78 (br s. 1H), 2.79 (s, 3 H). Massspectrum (MALDI-TOF, CHCA matrix, m/z): Calcd. for C₁₆H₁₃N₄O₂S₄F₃, 479.0(M+H), found 479.5.

EXAMPLE 137

a) Methyl4-(4-{4-{4-(toluenesulfonyl)amino]phenyl}(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxylate:Methyl4-(4-(4-aminophenyl)(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxylate(33 mg, 0.09 mmol) was dissolved in dry dichloromethane (5 mL). To this,N-methyl morpholine (10 μL, 0.09 mmol) and p-toluenesulfonyl chloride(17 mg, 0.09 mmol) was added and the mixture was stirred at roomtemperature for 5 days. Workup was carried out as in Example 134, step(c). Trituration with dichloromethane and methanol gave methyl4-(4-{4-[(toluenesulfonyl)amino]phenyl}(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxylate(20 mg, 43%) as a brown solid. ¹H-NMR (DMSO-d₆; 300 MHz) δ 10.39 (s,1H), 8.19 (s, 1H), 8.05 (s, 1H), 7.91 and 7.18 (AB quartet, 2H, J=8.7Hz), 7.68 and 7.35 (AB quartet, 2H, J=8.2 Hz), 3.85 (s, 3H), 2.74 (s,3H), 2.27 (s, 3H). Mass spectrum (MALDI-TOF, CHCA matrix, m/z): Calcd.for C₂₃H₂₀N₂O₄S₄, 517.2 (M+H), found 517.0.

b)4-(4-(4-[(Toluenesulfonyl)amino]phenyl}(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxamidine:Methyl 4-(4-{4-[(toluenesulfonyl)amino]phenyl}(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxylate (15 mg, 0.029mmol) was treated in a manner similar to that for Example 10, step (b),to give4-(4-{4-[(toluenesulfonyl)amino]phenyl}(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxamidine(17.9 mg, 81%) as a light brown solid. ¹H-NMR (DMSO-d₆; 300 MHz) δ 8.94(br s, 0.4H), 8.66 (s, 1H), 8.60 (br s, 0.3 H), 8.08 (s, 1H), 7.93 and7.20 (AB quartet, 2H, J=8.7 Hz), 7.68 and 7.35 (AB quartet, 2H, J=8.2Hz), 2.77 (s, 3H), 2.33 (s, 3H). Mass spectrum (MALDI-TOF, CHCA matrix,m/z): Calcd. for C₂₂H₂₀N₄O₂S₄: 501.1 (M+H), found 501.1.

EXAMPLE 138

a) Methyl4-[4-(4-chlorophenyl)(1,3-thiazol-2-yl)]-5-(methylsulfinyl)thiophene-2-carboxylate:To a stirred solution of 764 mg (2 mmol) of methyl4-[4-(4-chlorophenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxylate(Maybridge, Cornwall, UK) dissolved in 1,1,1,3,3,3-hexafluoroisopropanol(2.5 mL) was added 30% hydrogen peroxide (0.45 mL, 4 mmol). Thissolution was stirred for 45 h at room temperature. Dichloromethane (10mL) was added after 2 hours. Additional hydrogen peroxide (2×0.45 mLportions) was added after 4 hours and 24 hours. The mixture was quenchedwith 10% sodium sulfite in brine (4 mL). The organic layer wasseparated, dried over anhydrous sodium sulfate, and the solvents removedin vacuum. Column chromatography on silica gel (45 g), eluting withdichloromethane:methanol 99/1 (v:v) gave methyl4-[4-(4-chlorophenyl)(1,3-thiazol-2-yl)]-5-(methylsulfinyl)thiophene-2-carboxylate(720 mg, 90%) as a solid. ¹H-NMR (DMSO-d₆; 300 MHz) δ 8.37 (s, 1H), 8.30(s, 1H), 8.05 and 7.52 (AB quartet, 2H, J=8.6 Hz), 3.91 (s, 3H), 3.16(s, 3H). Mass spectrum (MALDI-TOF, GA matrix, m/z): Calcd. forC₁₆H₁₂NO₃S₃Cl:398.0 (M+H), found 397.8.

b)4-4-(4-Chlorophenyl)(1,3-thiazol-2-yl)]-5-(methylsulfinyl)thiophene-2-carboxamidine:Methyl4-[4-4-chlorophenyl)(1,3-thiazol-2-yl)]-5-(methylsulfinyl)thiophene-2-carboxylate(100 mg, 0.25 mmol) was treated in a manner similar to that for Example10, step (b), to give, after preparative thin layer chromatographypurification eluting with dichloromethane:methanol:acetic acid 9/1/0.5(v:v:v),4-[4-(4-chlorophenyl)(1,3-thiazol-2-yl)]-5-(methylsulfinyl)thiophene-2-carboxamidine(18.2 mg, 19%) as a solid. ¹H-NMR (DMSO-d₆; 300 MHz) δ 8.33 (s, 1H),8.22 (s, 1H), 8.05 and 7.57 (AB quartet, 2H,J=8.6 Hz), 3.12 (s, 3H).Mass spectrum (MALDI-TOF, CHCA matrix m/z): Calcd. for C₁₅H₁₂N₃OS₃Cl382.0 (M+H), found 382.1.

EXAMPLE 139

a) Methyl 4-cyano-5-(metltylsulfonyl)thiophene-2-carboxylate: To astirred solution of (4.5 g, 21 mmol) of methyl4-cyano-5-methylthiothiophene-2-carboxylate(Maybridge, Cornwall, UK) wasdissolved in dichloromethane (250 mL) and treated withm-chloroperbenzoic acid (15.3 g, 90 mmol) at room temperature for 2.25h. The mixture was filtered and the solid washed with dichloromethane(2×50 mL). The filtrate was washed with sodium bicarbonate (2×100 mL),sodium thiosulfate (100 mL), sodium bicarbonate (100 mL), water (100mL), brine (100 mL), and dried over anhydrous sodium sulfate. Thesolvent was removed in vacuo to give methyl4-cyano-5-(methylsulfonyl)thiophene-2-carboxylate (4.91 g, 95%) as asolid. ¹H-NMR (DMSO-d₆; 300 MHz) δ 8.44 (s, 1H), 3.91 (s, 3H), 3.58 (s,3H).

b) Methyl 4-cyano-5-methoxythiophene-2-carboxylate: Methyl4-cyano-5-(methylsulfonyl)thiophene-2-carboxylate (2 g, 8 mmol) wasrefluxed with 0.5 M sodium methoxide in methanol (16 mL) for 15 minutes.The solution was cooled, the crystallized solid collected on a Buichnerfunnel and washed with methanol (50 mL) to give methyl4-cyano-5-methoxythiophene-2-carboxylate (1.145 g, 73%) as a solid.¹H-NMR (DMSO-d₆; 300 MHz) δ 8.87 (s, 1H) 4.19 (s, 3H), 3.82 (s. 3H).

c) Methyl 4-(aminothioxomethyl)-5-methoxythiophene-2-carboxylate: Methyl4-cyano-5-methoxythiophene-2-carboxylate (1 g, 5 mmol) was dissolved indry methanol (150 mL) and triethylamine (3.5 mL, 25.4 mmol) was added.After degassing the solution with argon for 10 minutes, hydrogen sulfidegas was bubbled through the solution for 5 h. After stirring 18 h atroom temperature, the solution was degassed by bubbling argon (6 h),concentrated to 20 mL and acetone (20 mL) was added. The dark solid wascollected on a Buichner fimnel and washed with acetone. Recrystallizesolid from hot ethanol (15 mL) to give methyl4-(aminothioxomethyl)-5-methoxythiophene-2-carboxylate (683 mg, 59%) asa brown oil. Mass spectrum (MALDI-TOF, CHCA matrix, m/z): Calcd. forC₈H₉NO₃S₂ 232.0 (M+H), found 232.4

d) Methyl5-methoxy-4-(4-phenyl(1,3-thiophene-2-yl))thiophene-2-carboxylate: Asolution of 400 mg (1.73 mmol) of methyl4-(aminothioxomethyl-5-methoxythiophene-2-carboxylate was reacted with345 mg (1.73 rnnol) of 2-bromoacetophenone (Aldrich, Milwaukee, Wis.,USA) in a manner similar to Example 8, step (a) to give methyl5-methoxy-4-(4-phenyl(1,3-thiazol-2-yl))thiophene-2-carboxylate (56 mg,10%) as a solid. ¹H-NMR (DMSO-d₆; 300 MHz) δ 8.22 (s, 1H), 8.14 (s, 1H),8.05 (m, 2H), 7.47 (m, 2H), 7.36 (m, 1H), 4.26 (s, 3H), 3.85 (s, 3H).

e) 5-Methoxy-4-(4-phenyl(1,3-thiazol-2-yl))thiophene-2-carboxamidine:Methyl 5-methoxy-4-(4-phenyl(1,3-thiazol-2-yl))thiophene-2-carboxylate(55 mg, 0.16 mmol) was treated in a manner similar to that for Example10, step (b), to give5-methoxy-4-(4-phenyl(1,3-thiazol-2-yl))thiophene-2-carboxamidine (36mg, 69%) as a yellow solid. ¹H-NMR (DMSO-d₆; 300 MHz) δ 9.34 (br s, 2H),8.94 (br s, 2H), 8.70 (s, 1H), 8.20 (s, 1H), 8.07 (m, 2H), 7.49 (m, 2H),7.38 (m, 1H), 4.32 (s, 3H). Mass spectrum (MALDI-TOF, CHCA matrix, m/z):Calcd. for C₁₅H₁₃N₃OS₂ 316.5 (M+H), found 316.1

EXAMPLE 140

a) Methyl 4-cyano-5-(4-methoxyphenyl)methylthio]thiophene-2-carboxylate:To a stirred solution of 2.5 g (10 mmol) of methyl4-cyano-5-(methylsulfonyl)thiophene-2-carboxylate (Example 139, step(a)) in dry methanol (15 mL) was added p-methoxybenzylmercaptan (3.8 mL,28 mmol) and triethylamine (1.4 mL, 10 mmol). This solution was refluxedfor 15 min and cooled. The resulting solid was collected on a buichnerfunnel and washed with methanol (2×25 mL) to methyl4-cyano-5-[(4-methoxyphenyl)methylthio]thiophene-2-carboxylate (2.84 g,89%) as a solid.

b) Methyl4-(aminothioxomethyl)-5-[(4-methoxyphenyl)methylthio]thiophene-2-carboxylate:Methyl 4-cyano-5-[(4-methoxyphenyl)methylthio]thiophene-2-carboxylate(2.5 g, 7.8 mmol) was treated as in Example 139, step (c) to give methyl4-(aminothioxomethyl)-5-[(4-methoxyphenyl)methylthio]thiophene-2-carboxylate(1.32 g, 48%) as a solid. ¹H-NMR (DMSO-d₆; 300 MHz) δ 9.64 (s, 1H), 9.28(s, 1H), 8.08 (s, 1H), 7.35 and 6.92 (AB quartet, 2H, J=8.7 Hz), 4.27(s, 2H), 3.82 (s, 3H), 3.75 (s, 3H).

c) Methyl5-(methoxyphenylthio)-4-(4-phenyl(1,3-thiazol-2-yl))thiophene-2-carboxylate:A solution of 1.2 g (3.4 mmol) of methyl4-(aminothioxomethyl)-5-[(4-methoxyphenyl)methylthio]thiophene-2-carboxylatewas reacted with 676 mg (3.4 mmol) of 2-bromoacetophenone (Aldrich,Milwaukee, Wis., USA) in a manner similar to Example 8, step (a) to givemethyl5-(methoxyphenylthio)-4-(4-phenyl(1,3-thiazol-2-yl))thiophene-2-carboxylate(755 mg, 49%) as a solid. ¹H-NMR (DMSO-d₆; 300 MHz) δ 8.26 (s, 1H), 8.22(s, 1H), 8.04 (m, 2H), 7.48 (m, 2H), 7.38 (m, 1H), 7.33 and 6.89 (ABquartet, 2H, J=8.7 Hz), 4.40 (s, 2H), 3.86 (s, 3H), 3.72 (s, 3H).

d)5-(Methyloxyphenylthio)-4-(4-phenyl(1,3-thiazol-2-yl))thiophene-2-carboxamidine:Methyl5-(methoxyphenylthio)-4-(4-phenyl(1,3-thiazol-2-yl))thiophene-2-carboxylate(100 mg, 0.22 mmol) was treated in a manner similar to that for Example10, step (b), to give5-methoxy-4-(4-phenyl(1,3-thiazol-2-yl))thiophene-2-carboxamidine (94mg, 91%) as an orange solid. ¹H-NMR (DMSO-d₆; 300 MHz) δ 9.49 (br s,2H), 9.15 (br s, 2H), 8.70 (s, 1H), 8.26 (s, 114), 8.07 (m, 214), 7.49(m, 2H), 7.40 (m, 1H), 7.35 and 6.90 (AB quartet, 2H, J=8.7 Hz), 4.41(s, 2H), 3.73 (s, 3H). Mass spectrum (MALDI-TOF, CHCA matrix, m/z):Calcd. for C₂₂H₁₉N₃OS₃ 438.5 (M+H), found 438.1.

EXAMPLE 141

a) Methyl4-[4-(4-chlorophenyl)(1,3-thiazol-2-yl)]-5-(methylsulfonyl)thiophene-2-carboxylate:To a stirred solution of 1 g (2.6 mmol) of methyl4-[4-(4-chlorophenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxylate(Maybridge, Cornwall, UK) was dissolved in dry dichloromethane (50 mL)and treated with m-chloroperbenzoic acid (1.94 g, 11.3 mmol) at roomtemperature for 1.5 h. The solution was filtered and the solid washedwith dichloromethane. The filtrate was washed with sodium bicarbonatesolution (2×20 mL), sodium thiosulfate solution (20 mL), sodiumbicarbonate solution (20 mL), brine (20 mL), and dried over anhydroussodium sulfate. The solvent was removed in vacuo to give methyl4-[4-(4-chlorophenyl)(1,3-thiazol-2-yl)]-5-(methylsulfonyl)thiophene-2-carboxylate(826 mg, 77%) as a tan solid. Mass spectrum (MALDI-TOF, CHCA matrix,m/z): Calcd. for C₁₆H₁₂NO₄S₃Cl 414.0 (M+H), found 414.8.

b)4-[4-(4-Chlorophenyl)(1,3-thiazol-2-yl)]-5-(methylsulfonyl)thiophene-2-carboxamidine:Methyl4-[4-(4-chlorophenyl)(1,3-thiazol-2-yl)]-5-(methylsulfonyl)thiophene-2-carboxylate(200 mg, 0.4 mmol) was treated in a manner similar to that for Example10, step (b), to give4-[4-(4-chlorophenyl)(1,3-thiazol-2-yl)]-5-(methylsulfonyl)thiophene-2-carboxamidine(85 mg, 53%) as a yellow solid.

c)4-[4-(4-Chlorophenyl)(1,3-thiazol-2-yl)]-5-(phenylmethylthio)thiophene-2-carboxamidine:A stirred solution of 80 mg (0.2 mmol) of4-[4-(4-chlorophenyl)(1,3-thiazol-2-yl)]-5-(methylsulfonyl)thiophene-2-carboxamidinebenzylmercaptan (115 μL, 0.980 μmol) was treated in a manner similar to thatfor Example 140, step (a) to give, after silica gel columnchromatography (20 g) eluting with dichloromethane:methanol:acetic acid9/1/0.5 (v:v:v),4-[4-(4-chlorophenyl)(1,3-thiazol-2-yl)]-5-(phenylmethylthio)thiophene-2-carboxamidine(75 mg, 85%) as a pale orange solid. ¹H-NMR (DMSO-d₆; 300 MHz) δ 9.44(br s. 2H), 9.03 (br s, 2H), 8.67 (s, 114), 8.33 (s, 1H), 8.08 and 7.56(AB quartet, 2H, J=8.7 Hz), 7.54-7.17 (m, 5H), 4.45 (s, 2H). Massspectrum (MALDI-TOF, CHCA matrix. m/z): Calcd. for C₂₁,H₁₆N₃S₃Cl 442.0(M+H), found 442.7.

EXAMPLE 142

a) 1-[5-(tert-Butyl)-2-methyl(3-furyl)]-2-bromoethan-1-one: A solutionof 1 g (5 mmol) of 5-(tert-butyl)-2-methylfuran-3-carbonyl chloride(Maybridge, Cornwall, UK) dissolved in dry acetonitrile (4 mL) and 6.25mL (12.5 mmol) of 2 M trimethylsilyldiazomethane in hexanes (Aldrich,Milwaukee, Wis.) was stirred 1.75 h at room temperature and the mixturewas cooled on an ice bath for 5 min. To this, 30% hydrogen bromide inacetic acid (2 mL, 10 mmol) was added dropwise over 10 min. This wasstirred an additional 20 minutes on an ice bath. Evaporation of thesolvents gave 1-[5-(tert-butyl)-2-methyl(3-furyl)]-2-bromoethan-1-one (1g, 77%) as a brown oil. ¹H-NMR (DMSO-d₆; 300 MHz) δ 6.50 (s, 1H),4.57(s, 2H), 2.52 (s, 1H), 1.24 (s, 9H). Mass spectrum (LCA, m/z):Calcd. for C₁₁H₁₅O₂Br, 259.1 and 261.1 (M+H), found 259.1 and 261.1.

b) Methyl4-{4-[5-(tert-butyl)-2-methyl(3-furyl)](1,3-thiazol-2-yl)}-5-methylthiothiophene-2-carboxylate:A solution of 955 mg (3.86 mmol) of methyl4-(aminothioxomethyl)-5-methylthiothiophene-2-carboxylate (Maybridge,Cornwall, UK) was reacted with 1 g (3.86 mmol) of1-[5-(tert-butyl)-2-methyl(3-furyl)l-2-bromoethan-1-one (1 g) in amanner similar to Example 8, step (a) to give methyl4-{4-[5-(tert-butyl)-2-methyl(3-furyl)](1,3-thiazol-2-yl)}-5-methylthiothiophene-2-carboxylate(999 mg, 64%) as a red-brown solid. ¹H-NMR (DMSO-d₆; 300 MHz) δ 8.14 (s,1H), 7.74 (s, 1H), 6.46 (s, 1H), 3.86 (s, 3H), 2.74 (s, 3H), 2.66 (s,3H), 1.27 (s, 9H). Mass spectrum (MALDI-TOF, CHCA matrix, m/z): Calcd.for C₁₉H₂₁NO₃S₃, 408.1 (M+H), found 408.0.

c)4-{4-[5-(tert-Butyl)-2-methyl(3-furyl)](1,3-thiazol-2-yl)}-5-methylthiothiophene-2-carboxamidine:Methyl4-{4-[5-(tert-butyl)-2-methyl(3-furyl)](1,3-thiazol-2-yl)}-5-methylthiothiophene-2-carboxylate(940 mg, 2.3 nmmol) was treated in a manner similar to that for Example10, step (b) to give4-{4-[5-(tert-butyl)-2-methyl(3-furyl)](1,3-thiazol-2-yl)}-5-methylthiothiophene-2-carboxamidine(930 mg, quantitive yield) as a yellow solid. ¹H-NMR (DMSO-d₆; 300 MHz)δ 9.42 (br s, 2H), 9.03 (br s, 211), 8.59 (s, 1H), 7.77 (s, 1H), 6.47(s, 1H), 2.78 (s, 3H), 2.68 (s, 3H), 1.27 (s, 9H1). Mass spectrum(MALDI-TOF, CHCA matrix, n/z): Calcd. for C₁₈H₂₁N₃OS₃, 392.1 (M+H),found 392.1.

EXAMPLE 143

a) 1-[3-(tert-Butyl)-1-benzylpyrazol-5-yl]-2-bromoetlian-1-one: Asolution of 1 g (3.6 mmol) of 3-(tert-butyl)-1-benzylpyrazole-5-carbonylchloride (Maybridge, Cornwall, UK) was dissolved in dry acetonitrile (4mL) and 4.5 mL (9 mmol) of 2 M trimethylsilyldiazomethane in hexanes(Aldrich, Milwaukee, Wis., USA) was added. After stirring 1 h 20 min atroom temperature, the mixture was cooled on an ice bath for 5 min. Tothis, 30% hydrogen bromide in acetic acid (2 mL, 10 rnmol) was addeddropwise over 15 min. This was stirred an additional 15 minutes on anice bath. Filtration of the precipitated solid and evaporation of thesolvents gave 1-[3-(tert-butyl)-1-benzylpyrazol-5-yl]-2-bromoethan-1-one(1.47 g, quantitive yield) as an orange solid. ¹H-NMR (DMSO-d₆; 300 MHz)δ 7.33-7.06 (m, 5H), 7.08 (s, 11H), 5.64 (s, 2H), 4.57 (s, 2H), 1.28 (s,9H). Mass spectrum (MALDI-TOF, CHCA matrix, m/z): Calcd. forC₁₆H₁₉N₂OBr, 335.1 and 337.1 (M+H), found 335.6 and 337.6.

b) Methyl4-{4-[3-(tert-Butyl)-1-benzylpyrazol-5-yl](1,3-thiazol-2-yl)}-5-methylthiothiophene-2-carboxylate:A solution of 823 mg (3.3 mmol of methyl4-(aminothioxomethyl)-5-methylthiothiophene-2-carboxylate (Maybridge,Cornwall, UK) was reacted with 1.36 g (3.3 mmol) of1-[3-(tert-butyl)-1-benzylpyrazol-5-yl]-2-bromoethan-1-one in a mannersimilar to Example 8, step (a) to give methyl4-{4-[3-(tert-butyl)-1-benzylpyrazol-5-yl](1,3-thiazol-2-yl)}-5-methylthiothiophene-2-carboxylate(1.25 g, 79%) as a crystalline solid. ¹H-NMR (DMSO-d₆; 300 MHz) δ 8.11(s, 1H), 8.05 (s, 1H), 7.28-6.99 (m, 5H), 6.70 (s, 1H), 5.88 (s, 2H),3.86 (s, 3H), 2.70 (s, 3H), 1.30 (s, 9H). Mass spectrum (MALDI-TOF, CHCAmatrix, m/z): Calcd. for C₂₄H₂₅N₃O₂S₃, 484.1 (M+H), found 483.9.

c)4-{4-[3-(tert-Butyl)-1-benzylpyrazol-5-yl(1,3-thiazol-2-yl)}-5-methylthiothiophene-2-carboxamidine:Methyl4-{4-[3-(tert-butyl)-1-benzylpyrazol-5-yl](1,3-thiazol-2-yl)}-5-methylthiothiophene-2-carboxylate(1.2 mg, 2.6 mmol) was treated in a manner similar to that for Example10, step (b) to give4-{4-[3-(tert-butyl)-1-benzylpyrazol-5-yl](1,3-thiazol-2-yl)}-5-methylthiothiophene-2-carboxamidine(1.21 g, quantitive yield) as a yellow solid. ¹H-NMR (DMSO-d₆; 300 MHz)δ 9.43 (br s, 1H), 9.07 (br s, 1H), 8.60 (s, 1H), 8.04 (s, 1H),7.37-6.97 (m, 5H), 6.70 (s, 1H), 5.92 (s, 2H), 2.73 (s, 3H), 1.30 (s,9H). Mass spectrum (MALDI-TOF, CHCA matrix, m/z): Calcd. for C₂₃H₂₅N₅S₃,468.1 (M+H), found 468.1.

EXAMPLE 144

a) 4-Bromo-5-methylthiophene-2-carboxylic acid: A stirred solution of 1g (3.9 mmol) of 2-methyl-3,5-dibromothiophene (prepared by the method ofKano, S.et al., Heterocycles 20(10):2035, 1983) in dry tetrahydrofuran(10 mL) was cooled to −78° C. and 2 M n-butyllithium in cyclohexane(1.93 mL, 3.87 mmol) was added over 3 min. After stirring 3 min at −78°C., the mixture was added to tetrahydrofuran (100 mL) with dry icesuspended. This mixture was allowed to stir and warm to roomtemperature. To this, 6 hN hydrochloric acid (50 mL) was addedcarefully. Then, water (50 mL) was added and the layers were separated.The aqueous layer was extracted with diethyl ether (4×30 mL). Thecombined organic layers were washed with water, brine, and dried overanhydrous sodium sulfate. The solvents were removed in vacuo to give an85/15 mixture of 4-bromo-5-methylthiophene-2-carboxylic acid and5-bromothiophene-2-carboxylic acid (780 mg, 90%) as a tan solid. ¹H-NMR(DMSO-d₆; 300 MHz) δ 13.33 (br s, 1H), 7.62 (s, 1H), 7.56 and 7.34 (ABquartet, 0.35H, J=3.9 Hz), 2.41 (s, 3H). Gas Chromotography/Massspectroscopy (mn/z): Calcd. for C₆H₅O₂SBr, 220.9 and 222.9 (M+H), found221.3 and 223.3. Calcd. for C₅H₃O₂SBr, 206.9 and 208.9 (M+H), found207.3 and 209.3.

b) Metlzyl 4-bromo-5-methylthiophene-2-carboxylate: A solution of 780 mg(3.5 mmol) of an 85/15 mixture of 4-bromo-5-methylthiophene-2-carboxylicacid and 5-bromothiophene-2-carboxylic acid was dissolved in methanol(50 mL) and treated with 9 ml (18 mmol) 2 M trimethylsilyldiazomethanein hexanes (Aldrich, Milwaukee, Wis., USA). Evaporation of the solventsgave an 8/2 mixture of methyl 4-bromo-5-methylthiophene-2-carboxylateand methyl 5-bromothiophene-2-carboxylate (858 mg, quantitive yield) asa brown oil. Gas Chromotography/Mass spectroscopy (m/z): Calcd. forC₇H₇O₂SBr, 234.9 and 236.9 (M+H), found 235.3 and 237.3. Calcd. forC₆H₄O₂SBr, 220.9 and 222.9 (M+H), found 221.3 and 223.3.

c) Methlyl 4-cyano-5-methylthiophene-2-carboxylate: A solution of an 8/2mixture of 823 mg (3.5 mmol) of methyl4-bromo-5-methylthiophene-2-carboxylate and methyl5-bromothiophene-2-carboxylate was dissolved in dry dimethylformamide (5mL) and refluxed with copper cyanide (345 mg, 3.9 mmol) for 7 hours. Thecooled solution was poured into 0.1 M aqueous sodium cyanide solution(200 mL) and extracted with diethyl ether (5×30 mL). The organic layerswere washed with brine (2×30 mL), dried over anhydrous sodium sulfate,and the solvents removed in vacuo. The resulting brown solid waspurified by column chromatography on silica gel eluting withhexanes:ethyl acetate 9/1 (v:v) to give a 95/5 mixture of methyl4-cyano-5-methylthiophene-2-carboxylate and methyl5-methylthiophene-2-carboxylate (369 mg, 68%) as a yellow solid. ¹H-NMR(DMSO-d₆; 300 MHz) δ 8.06 (s, 1H), 8.05 and 7.90 (2H, 0.1 H, J=4.0 Hz,minor component), 3.87 (s, 3H, minor component), 3.84 (s, 3H) 2.68 (s,3H).

d) Methyl 4-(aminothtioxomethyl)-5-methylthiophene-2-carboxylate: Astirred solution of 804 mg (4.4 mmol) of methyl4-cyano-5-methylthiophene-2-carboxylate was treated in a manner similarto Example 139, step (c) to give, after fractional crystallizationethanol of the unreacted starting nitrile, a 2:3 ratio of methyl4-(aminothioxomethyl)-5-methylthiophene-2-carboxylate and methyl4-cyano-5-methylthiophene-2-carboxylate (457 mg, 48%) as a light brownsolid. ¹H-NMR (DMSO-d₆; 300 MHz) δ 9.93 (br s, 1H, minor), 9.34 (br s,1H, minor), 8.06 (s, 1H, major), 7.77 (s, 1H, minor component), 3.84 (s,3H, minor), 3.81 (s, 3H, major), 2.68 (s, 3H, major), 2.61 (s, 2H,minor). Mass spectrum (MALDI-TOF, CHCA matrix, m/z): Calcd. forC₈H₉NO₂S₂ 216.0 (M+H), found 216.4.

e) Methyl5-methyl-4-(4-phenyl(1,3-thiazol-2-yl))thiophene-2-carboxylate: Asolution of 200 mg (0.93 mmol) of methyl4-(aminothioxomethyl)-5-methylthiophene-2-carboxylate was reacted with185 mg (0.93 mmol) of 2-bromoacetophenone in a manner similar to Example8, step (a) to give, after purification by preparative thin layerchromatography eluting with hexanes:ethyl acetate 7/3 (v:v), a mixtureof methyl 5-methyl-4-(4-phenyl(1,3-thiazol-2-yl))thiophene-2-carboxylateand methyl 4-cyano-5-methylthiophene-2-carboxylate (96 mg, 36%) as asolid.

f) 5-Methyl-4-(4-phenyl(1,3-thiazol-2-yl))thiophene-2-carboxamidine:Methyl-4-(4-phenyl(1,3-thiazol-2-yl))thiophene-2-carboxylate (64 mg,0.23 mmol) was treated in a manner similar to Example 10, step (b) togive, after preparative high pressure liquid chromatography (Dynamax C18column, 300 Å pore size, 10 μm particle size, 40% to 100% acetonitrileover 30 minutes in 0.1% aqueous trifluoroacetic acid)5-methyl-4-(4-phenyl(1,3-thiazol-2-yl))thiophene-2-carboxamidine (0.6mg, 0.9%) as an an off-white solid. ¹H-NMR (CD₃OD, 300 MHz) δ 8.44 (s,1H), 8.02 (m, 2H), 7.92 (s, 1H), 7.45 (m, 2H). 7.36 (m, 1H), 2.96 (s,3H). Mass spectrum (MALDI-TOF, CHCA matrix, m/z): Calcd. for C₁₅H13N₃S₂300.1 (M+H), found 300.6.

g) 5-(4-Phenyl-1,3-thiazol-2-yl)thiophene-2-carboxamide: From the HPLCpurified mixture in the previous step was isolated5-(4-phenyl-1,3-thiazol-2-yl)thiophene-2-carboxamide as an off-whitesolid (2 mg). ¹H-NMR (Methanol-d₄; 300 MHz) δ 7.99 (m, 2H), 7.97 (s,1H), 7.95 and 7.78 (AB quartet, 2H, J=4.2 Hz), 7.48-7.35 (m, 3H). Massspectrum (MALDI-TOF, CHCA matrix, m/z): Calcd. for C₁₄H₁₁N₃S₂286.0(M+H), found 286.2.

EXAMPLE 145

a) Methyl4-[4-(3,4-dimethoxyphenyl)(1,3-thiazol-2-yl)]-5-metltylthiophene-2-carboxylate:A solution of 257 mg (0.48 mmol, based on a mixture containing 60%nitrile) of methyl 4-(aminothioxomethyl)-5-methylthiophene-2-carboxylatewas reacted with 124 mg (0.48 nmuol) of 2-bromo-(3′,4′-dimethoxy)-acetophenone (Example 31, step (a)) was reacted in amanner similar to Example 8, step (a) to give methyl4-[4-(3,4-dimethoxyphenyl)(1,3-thiazol-2-yl)]-5-methylthiophene-2-carboxylate(95 mg, 53%) as a solid. Mass spectrum (MALDI-TOF, CHCA matrix, m/z):Calcd. for C₁₈H₁₇NO₄S₂ 376.1 (M+H), found 376.3.

b)4-[4-(3,4-Dimethoxyphenyl)(1,3-thiazol-2-yl)]-5-metlzylthioplhene-2-carboxamide:Methyl4-[4-(3,4-dimethoxyphenyl)(1,3-thiazol-2-yl)]-5-methylthiophene-2-carboxylate(95 mg, 0.25 mmol) was treated in a manner similar to Example 10, step

(b) to give4-[4-(3,4-dimethoxyphenyl)(1,3-thiazol-2-yl)]-5-methylthiophene-2-carboxamide(8 mg, 9%) as a yellow solid. ¹H-NMR (Methanol-d₄; 300 MHz) δ 8.42 (s,1H), 7.81 (s, 1H), 7.61 (m, 2H), 7.03 (m, 1H), 3.92 (s, 3H), 3.88 (s,3H), 2.95 (s, 3H). Mass spectrum (MALDI-TOF, ClICA matrix, m/z): Calcd.for C₁₇H₁₇N₃O₂S₂ 360.1 (M+H), found 360.2.

EXAMPLE 146

a) 4-Bromo-5-methylthiophene-2-carboxylic acid: A solution of 27.65 g(108 mmol) of 2-methyl-3,5-dibromothiophene (prepared by the method ofKano, S.et al., Heterocycles 20(10):2035, 1983) was dissolved in drytetrahydrofturan (280 mL), cooled to −78 ° C. and 2 M n-butyl lithium incyclohexane (54 mL, 108 mmol) was added over 10 min. After stirring 20min at −78 ° C., dry carbon dioxide gas was bubbled through the solutionfor 1.5 h as the mixture was allowed to warm to room temperature. Tothis 6 N hydrochloric acid (100 mL) was added carefully. The layers wereseparated and the aqueous layer was extracted with diethyl ether (4×50mL). The combined organic layers were washed with brine, and dried overanhydrous sodium sulfate. The solvents were removed in vacuo to give4-bromo-5-methylthiophene-2-carboxylic acid (22.4 g, 94%) as anoff-white solid. ¹H-NMR (DMSO-d₆; 300 MHz) δ 13.34 (br s, 1H), 7.61 (s,1H), 2.41 (s, 3H).

b) Isopropyl 4-bromo-5-methylthiophene-2-carboxylate: A solution of 5 g(22.6 mmol) of 4-bromo-5-methylthiophene-2-carboxylic acid was dissolvedin dry dichloromethane (200 mL) and reacted with oxalyl chloride (2 mL,22.6 mmol) and dimethylformamide (100 μL) stirring on an ice bath for 30min and then at room temperature for 2.5 h. The solvents were removed invacuo and the residue was passed through silica gel, eluting off withhexanes:ethyl acetate 7/3 (v:v), ethyl acetate, and dichloromethane. Thesolvents were removed in vacuo and the resulting oil dissolved in drydichloromethane (100 mL). This solution was reacted with dry pyridine (9mL, 113 mmol) and dry isopropanol (40 mL, 522 mmol) for 88 h. Thesolvents were removed in vacuo and the residue partitioned betweensodium bicarbonate (150 mL) and dichloromethane (75 mL). The aqueouslayers were extracted with dichloromethanc (2×20 mL), and the combinedorganic layers were washed with sodium bicarbonate (30 mL), brine (30mL), and dried over anhydrous sodium sulfate. The solvents were removedin vacuo. The residue was purified by column chromatography eluting withhexanes:ethyl acetate 9/1 (v:v) to give isopropyl4-bromo-5-methylthiophene-2-carboxylate (1.91 g, 32%) as a pale yellowoil. ¹H-NMR (DMSO-d₆; 300 MHz) δ 7.66 (s, 1H), 5.07 (septet, 1H, J=6.2Hz), 2.42 (s, 3H), 1.29 (d, 6H, J=6.2 Hz). Mass spectrum (ESI, m/z):Calcd. for C₉H₁₁O₂SBr 264.2 (M+H), found 264.8.

c) Isopropyl 4-cyano-5-methylthiiophene-2-carboxylate: A stirredsolution of 1.9 g (7.3 mmol) of isopropyl4-bromo-5-methylthiophene-2-carboxylate was dissolved in drydimethylformamide (30 mL) and refluxed with copper cyanide (785 mg, 8.8mmol) for 16 hours. The cooled solution was poured into 0.1 M aqueoussodium cyanide solution (300 mL) and extracted with diethyl ether (4×40mL). The organic layers were washed with brine (2×40 mL), dried overanhydrous sodium sulfate, and the solvents removed in vacuo. Columnchromatography on silica gel eluting with hexanes:ethyl acetate 9/1(v:v), gave isopropyl 4-cyano-5-methylthiophene-2-carboxylate (960 mg,63%) as a yellow crystalline solid ¹H-NMR (DMSO-d₆; 300 MHz) δ 8.01 (s,1H), 5.09 (septet, 1H, J=6.2 Hz), 2.67 (s, 31H), 1.29 (d, 6H, J=6.2 Hz).

d) Isopropyl 4-(aminothioxomethyl)-5-methylthiophene-2-carboxylate: Astirred solution of 960 mg (4.59 mmol) of isopropyl4-cyano-5-methylthiophene-2-carboxylate was treated in a manner similarto Example 139, step (c) to give, after crystallization from diethylether, isopropyl 4-(aminothioxomethyl)-5-methylthiophene-2-carboxylate(623 mg, 56%) as a solid. ¹H-NMR (DMSO-d6; 300 MHz) δ 9.93 (br s, 1H),9.34 (br s, 1H), 7.54 (s, 1H), 5.07 (septet, 1H, J=6.2 Hz), 2.60 (s,3H), 1.29 (d, 6H, J=6.2 Hz). Mass spectrum (MALDI-TOF, GA matrix, m/z):Calcd. for C₁₀H₁₃NO₂S₂ 244.0 (M+H), found 243.8.

e) Isopropyl5-methyl-4-(4-phenyl(1,3-thiazol-2-yl))thiophene-2-carboxylate: Asolution of 375 mg (1.54 mmol) of isopropyl4-(aminothioxomethyl)-5-methylthiophene-2-carboxylate was reacted with307 mg (1.54 mmol) of 2-bromoacetophenone (Aldrich, Milwaukee, Wis.,USA) in a manner similar to Example 8, step (a) to give, aftercrystallization from methanol, isopropyl5-methyl-4-(4-phenyl(1,3-thiazol-2-yl))thiophene-2-carboxylate (347 mg,66%) as light brown needles. ¹H-NMR (DMSO-d₆; 300 MHz) δ 8.23 (s, 1H),8.09 (s, 1H), 8.05 (m, 2H), 7.49 (m, 2H), 7.38 (m, 1H), 5.13 (septet,1H, J=6.2 Hz), 2.86 (s, 3H), 1.33 (d, 6H, J=6.2 Hz). Mass spectrum (ESI,m/z): Calcd. for C₁₈H₁₇NO₂S₂ 344.1 (M+H), found 344.1.

f) 5-Methyl-4-(4-phenyl(1,3-thiazol-2-yl))thioplhene-2-carboxamidine:Isopropyl 5-methyl-4-(4-phenyl(1,3-thiazol-2-yl))thiophene-2-carboxylate(340 mg, 0.99 mmol) was treated in a manner similar to Example 10, step(b) to give5-methyl-4-(4-phenyl(1,3-thiazol-2-yl))thiophene-2-carboxamidine (360mg, quantitive yield) as a yellow solid. This material was dissolved indry methanol (20 mL) and treated with 1 M HCl (g) in diethyl ether.Evaporation of the solvents in vacuo and recrystallization from methanolgave the hydrochloride salt of5-methyl-4-(4-phenyl(1,3-thiazol-2-yl))thiophene-2-carboxamidine (252mg, 76%) as a light brown crystalline solid. ¹H-1-NMR (DMSO-d₆; 300 MHz)δ 9.45 (br s, 2H), 9.10 (br s, 2H), 8.56 (s, 1H), 8.27 (s, 1H), 8.06 (m,2H), 7.50 (m, 2H), 7.40 (m, 1H), 2.93 (s, 3H). Mass spectrum (ESI, m/z):Calcd. for C₁₅H₁₃N₃S₂ 300.1 (M+H), found 300.2.

EXAMPLE 147

a) 2-Methyl-5-[(methylethyl)oxycarbonyl]thiophene-3-carboxylic acid: Astirred mixture of 500 mg (2.39 mmol) of isopropyl2-methyl-3-cyanothiophene-5-carboxylate and tetrafluorophthalic acid(570 mg, 2.39 mmol) was heated in a glass bomb at 160° C. for 66 hours.The cooled residue was digested in hot chloroform (30 mL), treated withnorite, and filtered through celite. The celite was washed with hotchloroform (30 mL). The cooled chloroform extracts were filtered andextracted with saturated sodium bicarbonate (4×10 mL). The basicextracts were washed with chloroform, filtered through celite, andacidified to pH 1 with concentrated hydrochloric acid. The solid wascollected by filtration and washed with water (3×10 ml) to give2-methyl-5-[(methylethyl)oxycarbonyl]thiophene-3-carboxylic acid (288mg, 53%) as a light brown solid. ¹H-NMR (DMSO-d₆; 300 MHz) δ 13.03 (brs, 1H), 7.85 (s, 1H), 5.08 (septet, 1H, J=6.2 Hz), 2.71 (s, 3H), 1.29(d, 6H, J=6.2 Hz). Mass spectrum (ESI, m/z): Calcd. for C₁₀H₁₂O₄S 229.1(M+H), found 228.8

b) Isopropyl 4-(2-bromoacetyl)-5-methylthiophene-2-carboxylate: Astirred solution of 300 mg (1.3 mmol) of2-methyl-5-[(methylethyl)oxycarbonyl]thiophene-3-carboxylic acid wasdissolved in dry dichloromethane (10 mL) and treated with oxalylchloride (174 μL, 2 mmol) and dimethylformamide (50 μL). The mixture wasstirred at room temperature for 1.25 h, the solvents removed in vacuo,and the residue passed through silica gel (1 inch in a 60 mLsintered-glass Buchner funnel) and eluted off with dichloromethane (150mL). This material was treated in a manner similar to Example 142, step(a) to give isopropyl 4-(2-bromoacetyl)-5-methylthiophene-2-carboxylate(266 mg, 67%) as a solid.

c) Isopropyl4-(2-amino(1,3-thiazol-4-yl))-5-methylthiophene-2-carboxylate: Asolution of 260 mg (0.85 mmol) of isopropyl4-(2-bromoacetyl)-5-methylthiophene-2-carboxylate was reacted with 65 mg(0.85 mmol) of thiourea in a manner similar to Example 8, step (a) togive isopropyl4-(2-amino(1,3-thiazol-4-yl))-5-methylthiophene-2-carboxylate (257 mg,quantitive yield) as a white solid. ¹H-NMR (DMSO-d₆; 300 MHz) δ 7.90 (s,1H), 6.93 (s, 1H), 5.09 (septet. 1H, J=6.2 Hz), 2.61 (s, 3H), 1.29 (d,6H, J=6.2 Hz). Mass spectrum (ESI, m/z): Calcd. for C₁₂H₁₄N₂O₂S₂ 283.1(M+H), found 283.1

d) 4(2-Amino(1,3-thiazol-4-yl))-5-methylthiophene-2-carboxamidine:Isopropyl 4-(2-amino(1,3-thiazol-4-yl))-5-methylthiophene-2-carboxylate(240 mg, 0.85 mmol) was treated in a manner similar to Example 10, step(b) to give4-(2-amino(1,3-thiazol-4-yl))-5-methylthiophene-2-carboxamidine (20 mg,10%) as a solid. ¹H NMR (DMSO-d₆, 300 MHz): δ 9.30 (br s, 2H), 8.99 (bs,2H), 8.28 (s, 1H), 6.78 (s, 1H), 2.71 (s, 3H); Mass Spectrum (ESI, m/z)calcd. for C₉H₁₀N₄S₂, 238.8 (M+H), found 239.2.

EXAMPLE 148

a) 4-Bromo-5-ethylthiophene-2-carboxylic acid: A stirred solution of 10g (35 mmol) of 4,5-dibromothiophene-2-carboxylic acid (Lancaster,Windham, N.H., USA) in dry THF (100 mL) was cooled to −78 ° C. To this,35 mL (70 mmol) of 2.0 n-butyl]ithium in cyclohexane (Aldrich,Milwaukee, Wis., USA) was added dropwise over 15 min, and the reactionwas allowed to stir for 15 min at −78 ° C. The mixture was quenched withethyl iodide (2.8 mL, 35 mmol) and allowed to warm to room temperature.The mixture was carefully poured into 6N hydrochloric acid (100 mL) andextracted with diethyl ether (4×50 mL). The organic layers were washedwith water (2×50 mL), brine (50 mL), and dried over anhydrous sodiumsulfate. The solvents were removed in vacuo to give2-ethyl-3-bromo-thiophene-5-carboxylate (7 g, 85%) as a dark solid.¹H-NMR (DMSO-d₆; 300 MHz) δ 13.25 (br s, 1H), 7.62 (s, 1H), 2.80 (q, 2H,J=7.5 Hz), 1.23 (t, 3H, J=7.5 Hz).

b) Isopropyl 4-bromo-5-ethylthiophene-2-carboxylate: A solution of 7 g(30 mmol) of 4-bromo-5-ethylthiophene-2-carboxylic acid was dissolved indry dichloromethane (200 mL) and treated with oxalyl chloride (3.2 mL,36 mmol) and dimethylformamide (0.5 mL) for 18.5 h. The solvents wereremoved in vacuo and the residual brown oil was passed through silicagel (2 inches in a 350 mL scintered-glass Buchner funnel) and elutedwith 700 mL of hexanes:ethyl acetate 9/1 (v:v). The elutate wasconcentrated in vacuo and the oil dissolved in dry dichloromethane (200mL). This solution was treated with pyridine (12 mL, 150 mmol) and dryisopropanol (60 mL, 750 mmol) for 4 h at room temperature. The solventswere removed in vacuo and the residue partioned between dichloromethane(100 mL) and water (200 mL). The aqueous layers were extracted withdichloromethane (2×30 mL). The combined organic layers were extractedwith sodium bicarbonate (2×30 mL), brine (30 mL), and dried overanhydrous sodium sulfate. The solvent was removed in vacuo. Purificationby column chromatography on silica gel (250 g) eluting withhexanes:ethyl acetate 95/5 (v:v) gave isopropyl2-ethyl-3-bromo-thiophene-5-carboxylate (4 g, 48%) as a yellow oil.¹H-NMR (DMSO-d₆; 300 MHz) δ 7.66 (s, 1H), 5.89 (septet, 1H, J=6.2 Hz),2.80 (q, 2H, J=7.5 Hz), 1.29 (d, 6H, J=6.0 Hz), 1.24 (t, 3H, J=7.5 Hz).

c) Isopropyl 4-cyano-5-ethylthiophene-2-carboxylate: A stirred solutionof 4 g (14.4 mmol) of isopropyl 4-bromo-5-ethylthiophene-2-carboxylatewas refluxed in dry dimethylformamide (50 mL) with copper cyanide (1.94g, 22 mmol) for 6 hhours. The cooled mixture was poured into 0.1 Msodium cyanide (500 mL) and extracted with diethyl ether (4×50 mL). Theorganic layers were washed twice with brine (50 mL) and dried overanhydrous sodium sulfate. The solvents were removed in vacuo. Columnchromatography on silica gel (400 g), eluting with hexanes:ethyl acetate9/1 (v:v) gave isopropyl 2-ethyl-3-cyano-thiophene-5-carboxylate (1.7 g,53%) as a pale yellow oil. ¹H-NMR (DMSO-d₆; 300 MHz) δ 8.03 (s, 1H),5.10 (septet, 1H, J=6.2 Hz), 3.04 (q, 2H, J=7.5 Hz), 1.31 (t, 3H, J=7.5Hz), 1.30 (d, 6H1, J=6.2 Hz). Mass spectrum (ESI m/z): Calcd. forC₁₁H₁₃NO₂S 224.1 (M+H), found 224.0.

d) Isopropyl 4-(aminothioxomethyl)-5-ethylthiophene-2-carhoxylate: Astirred solution of 1.7 g (7.6 mmol) of isopropyl4-cyano-5-ethylthiophene-2-carboxylate was treated as in Example 139,step (c) to give isopropyl5-ethyl-4-(aminothioxomethyl)-5-ethylthiophene-2-carboxylate (1.45 g,74%) as a yellow solid. ¹H-NMR (DMSO-d₆; 300 MHz) δ 9.93 (br s, 1H),9.39 (br s, 1H), 8.04 (s, 1H), 5.08 (septet, 1H, J=6.2 Hz), 3.08 (q, 2H,J=7.5 Hz), 1.29 (d, 6H, J=6.2 Hz), 1.24 (t, 3H, J=7.5 Hz).

e) Isopropyl5-ethyl-4-(4-phenyl(1,3-thiazol-2-yl))thiophene-2-carboxylate: Asolution of 450 mg (1.75 mmol) of isopropyl5-ethyl-4-(aminothioxomethyl)-5-ethylthiophene-2-carboxylate was reactedwith 348 mg (1.75 mmol) of 2-bromoacetophenone (Aldrich, Milaukee, Wis.,USA) in a manner similar to Example 8, step (a) to give isopropyl5-ethyl-4-(4-phenyl(1,3-thiazol-2-yl))thiophene-2-carboxylate (303 mg,49%) as an off-white solid. ¹H-NMR (DMSO-d₆; 300 MHz) δ 8.22 (s, 1H),8.07 (s, 1H), 8.03 (m, 2H), 7.49 (m, 2H), 7.38 (m, 1H), 5.13 (septet,1H, J=6.2 Hz), 3.34 (q, 2H, J=7.4 Hz), 1.39 (t, 3H, J=7.4 Hz), 1.33 (d,6H, J=6.2 Hz). Mass spectrurn (ESI, m/z): Calcd. for C₁₉H₁₉NO₂S₂ 358.1(M+H), found 358.1.

f) 5-Ethyl-4-(4-phenyl(1,3-thiazol-2-yl))thiophtene-2-carboxamidine:Isopropyl 5-ethyl-4-(4-phenyl(1,3-thiazol-2-yl))thiophene-2-carboxylate(250 mg, 0.70 mmol) was treated in a manner similar to that for Example10, step (b), to give5-ethyl-4-(4-phenyl(1,3-thiazol-2-yl))thiophene-2-carboxamidine (148 mg,67%) as a yellow solid. ¹H-NMR (DMSO-d₆; 300 MHz) δ 9.44 (br s, 2H),9.07 (br s, 2H), 8.54 (s, 1H), 8.26 (s, 1H), 8.05 (m, 2H), 7.50 (m, 2H),8.70 (s, 1H), 7.40 (m, 1H), 3.44 (q, 2H, J=7.4 Hz), 1.42 (t, 3H, J=7.4Hz). Mass spectrum (ESI, m/z): Calcd. for C₁₆H₁₅N₃S₂ 314.1 (M+H), found314.2.

EXAMPLE 149

a) Isopropyl4-[4-(3-hydroxyphenyl)(1,3-thiazol-2-yl)]-5-methylthiophene-2-carboxylate:A solution of 1.97 g (8.1 mmol) of isopropyl4-(aminothioxomethyl)-5-methylthiophene-2-carboxylate was reacted with1.74 g (8.1 immol) of 3′-hydroxy-2-bromoacetophenone (Example 40, step(a)) were reacted in a manner similar to Example 8, step (a) to give,after column chromatography on silica gel eluting with hexane:ethylacetate 7/3 (v:v), crystallization from acetonitrile, andrecrystallization from hexanes, isopropyl4-[4-(3-hydroxyphenyl)(1,3-thiazol-2-yl)]-5-methylthiophene-2-carboxylate(1.4 g, 48%) as brown solid. ¹H-NMR (DMSO-d₆; 300 MHz) δ 9.57 (br s,1H), 8.14 (s, 1H), 8.08 (s, 1H), 7.46 (mn, 2H), 7.26 (m, 1H),), 6.78 (m,1H), 5.12 (septet, 1H, J=6.2 Hz), 2.85 (s, 3H), 1.33 (d, 6H, J=6.2 Hz).Mass spectrum (ESI, m/z): Calcd. for C₁₈H₁₇NO₃S₂ 360.1 (M+H). found360.1.

b)4-[4-(3-Hydroxyphenyl)(1,3-tihiazol-2-yl)]-5-methylthiophene-2-carboxamide:Isopropyl4-[4-(3-hydroxyphenyl)(1,3-thiazol-2-yl)]-5-methylthiophene-2-carboxylate(1.4 g, 3.89 mmol) was treated in a manner similar to Example 10, step(b) to give4-[4-(3-hydroxyphenyl)(1,3-thiazol-2-yl)]-5-methylthiophene-2-carboxamide(360 mg, 31%) as a brown solid. ¹H-NMR (DMSO-d₆; 300 MHz) δ 9.62 (br s,1H), 9.45 (br s, 2H), 9.09 (br s, 2H), 8.53 (s, 1H), 8.16 (s, 1H), 7.47(m, 2H), 7.27 (m, 1H), 6.80 (mn, 1H), 2.93 (s, 3H). Mass spectrum (ESI,m/z): Calcd. for C₁₅H₁₃N₃OS₂ 316.1 (M+H), found 316.2.

EXAMPLE 150

a)(tert-Butoxy)-N-({4-[4-(3-hydroxyphenyl)(1,3-thiazol-2-yl)]-5-methyl(2-thienyl)}iminomethyl)carboxamide:A stirred solution of 320 mg (1 mmol) of4-[4-(3-hydroxyphenyl)(1,3-thiazol-2-yl)]-5-methylthiophene-2-carboxamidewas dissolved in dry dimethylformamide (50 mL) and treated with 262 mg(1.2 mmol) of di-tert-butyl-dicarbonate (Acros, Pittsburgh, Pa., USA)and diisopropylethylamine (261 μL, 1.5 mmol) for 64 hours at roomtemperature. The mixture was poured into sodium bicarbonate solution(200 mL) and extracted with dichloromethane (6×30 mL). The organicextracts were washed twice with brine (50 mL) and dried over anhydroussodium sulfate. The solvents were in vacuo and column chromatography onsilica gel (100 g) eluting with dichloromethane:methanol 95/5 (v:v) gave(tert-butoxy)-N-({4-[4-(3-hydroxyphenyl)(1,3-thiazol-2-yl)]-5-methyl(2-thienyl)}iminomethyl)carboxamide(247 mg, 59%) as a yellow oil. ¹H-NMR (DMSO-d₆; 300 MHz) δ 9.56 (s, 1H),9.12 (br s, 2H), 8.47 (s, 1H), 8.09 (s, 1H), 7.46 (m, 2H), 7.26 (m, 1H),6.78 (m, 1H), 2.83 (s, 3H), 1.45 (s, 9H). Mass spectrum (ESI, m/z):Calcd. for C₂₀H₂₁N₃O₃S₂ 416.1 (M+H), found 415.7

b) Methyl2-{3-[2-(5-{[(tert-butoxy)carbonylamino]iminomethyl}-2-methyl-3-thienyl)-1,3-thiazol-4-yl]phenoxy}acetate:A stirred solution of 247 mg (0.595 mmol) of(tert-butoxy)-N-({4-[4-(3-hydroxyphenyl)(1,3-thiazol-2-yl)]-5-methyl(2-thienyl)}iminomethyl)carboxamidewas dissolved in dry dimethylformamide (4 mL) and treated with cesiumcarbonate (291 mg, 0.89 mmol) and methyl bromoacetate (136 mg, 0.89mmol) for 3 h at 60° C. The mixture was poured into water (50 mL) andextracted with dichloromethane (9×10 mL). The organic extracts werewashed with brine (10 mL) and dried over anhydrous sodium sulfate. Thesolvents were removed in vacuo and column chromatography on silica gel(50 g) eluting with dichloromethane:methanol 98/2 (v:v) gave methyl2-{3-[2-(5-{[(tert-butoxy)carbonylamino]iminomethyl}-2-methyl-3-thienyl)-1,3-thiazol-4-yl]phenoxy}acetate(178 mg, 61%) as an oil. Mass spectrum (ESI, m/z): Calcd. forC₂₃H₂₅N₃O₅S₂ 488.1 (M+H), 388.1 ((M-BOC)+H), found 487.8, 388.2.

c) Methyl2-{3-[2-(5-amidino-2-methyl-3-thienyl)-1,3-thiazol-4-yl]phenoxy}acetate:Methyl2-{3-[2-(5-{[(tert-butoxy)carbonylamino]iminomethyl}-2-methyl-3-thienyl)-1,3-thiazol-4-yl]phenoxy}acetate(15mg, 0.031 mmol) treated with dichloromethane:trifluoroacetic acid 1/1(v:v) with 2.5% water added at room temperature for 1.5 h. Removal ofthe solvents in vacuo gave methyl2-{3-[2-(5-amidino-2-methyl-3-thienyl)-1,3-thiazol-4-yl]phenoxy}acetate(8.1 mg, 52%) as a brown solid. ¹H-NMR (DMSO-d₆; 300 MHz) δ 9.38 (br s,2H), 8.94 (br s, 2H), 8.51 (s, 1H), 8.31 (s, 1H), 7.62 (m, 2H), 7.41 (m,1H), 6.96 (m, 1H), 4.89 (s, 2H), 3.72 (s, 3H), 2.92 (s, 3H). Massspectnim (ESI, m/z): Calcd. for C₁₈H₁₇N₃O₃S₂ 388.1 (M+H), found 388.3.

EXAMPLE 151

a)2-{3-[2-(5-{[(tert-Butoxy)carbonylamino]iminomethyl}-2-methyl-3-thienyl)-1,3-thiazol-4-yl]phenoxy}aceticacid: A stirred solution of 50 mg (0.11 mmol) of methyl2-{3-[2-(5-{[(tert-butoxy)carbonylamino]iminomethyl}-2-methyl-3-thienyl)-1,3-thiazol-4-yl]phenoxy}acetatewas dissolved in tetrahydrofuran (10 mL) and treated 2M aqueous sodiumhydroxide solution (2 mL) at room temperature for 1 h 10 min. Thesolvents were removed in vacuo. Purification by passing the solidthrough silica gel (1 inch in a 60 mL sintered-glass Buichner funnel)eluting with dichloromethane:methanol 8/2 (v:v) gave2-{3-[2-(5-{[(tert-butoxy)carbonylamino]iminomethyl}-2-methyl-3-thienyl)-1,3-thiazol-4-yl]phenoxy}aceticacid (44 mg, 88%) as a yellow solid. ¹H-NMR (DMSO-d₆; 300 MHz) δ 9.38(br s, 2H), 8.94 (br s, 2H), 8.51 (s, 1H), 8.31 (s, 1H), 7.62 (m, 2H),7.41 (m, 1H), 6.96 (m, 1H), 4.89 (s, 2H), 3.72 (s, 3H), 2.92 (s, 3H).Mass spectrum (ESI, m/z): Calcd. for C₂₂H₂₃N₃O₅S₂ 474.1 (M+H), 374.1((M-BOC)+H) found 374.2, 473.7.

b)2-{3-[2-(5-Amidino-2-methyl-3-thienyl)-1,3-thiazol-4-yl]phenoxy}aceticacid: Methyl2-{3-[2-(5-{[(tert-butoxy)carbonylamino]iminomethyl}-2-methyl-3-thienyl)-1,3-thiazol-4-yl]phenoxy}acetate(4 mg, 0.0084 mmol) was treated with dichloromethane:trifluoroaceticacid 1/1 (v:v) with 2.5% water added at room temperature for 2 h 35 min.Removal of the solvents in vacuo gave2-{3-[2-(5-amidino-2-methyl-3-thienyl)-1,3-thiazol-4-yl]phenoxy}aceticacid (2.9 mg, 71%) as a solid. Mass spectrum (ESI, m/z): Calcd. forC₁₇H₁₅N₃O₃S₂ 373.1 (M+H), found 374.2.

c) tert-Butyl4-(2-{3-[2-(5-{[(tert-butoxy)carbonylamino]iminomethyl}-2-methyl-3-thienyl)-1,3-thiazol-4-yl]phenoxy}acetyl)piperazinecarboxlate:A stirred solution of 40 mg (0.084 mmol) of2-{3-[2-(5-{[(tert-butoxy)carbonylamino]iminomethyl}-2-methyl-3-thienyl)-1,3-thiazol-4-yl]phenoxy}aceticacid dissolved in dry dimethylformamide (5 mL) was treated withhydroxybenzotriazole (23 mg, 0.17 mmol), 32 mg (0.17 mmol) ofN-tert-butoxycarbonyl-piperazine (Lancaster, Windham, N.H., USA), 65 mg(0.17 mmol) of O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetrarmethyluroniumhexafluorophosphate (HATU) at room temperature for 20 h. The mixture waspartitioned between dichloromethane (50 mL) and brine (50 mL). Theaqueous layers were extracted twice with dichloromethane (50 mL) and thecombined organic layers were washed with brine (50 mL) and dried overanhydrous sodium sulfate. The solvents were removed in vacuo.Purification preparative thin layer chromatography eluting withdichloromethane:methanol 95/5 (v:v) gave tert-butyl4-(2-{3-[2-(5-{[(tert-butoxy)carbonylamino]iminomethyl}-2-methyl-3-thienyl)-1,3-thiazol-4-yl]phenoxy}acetyl)piperazinecarboxylate(25 mg, 46%) as a white solid. ¹H-NMR (DMSO-d₆; 300 MHz) δ 9.13 (br s,2H), 8.50 (s, 1H), 8.20 (s, 1H), 7.63 (m, 2H), 7.39 (m, 1H), 6.95 (m,1H), 4.93 (s, 2H), 3.47-3.34 (m, 8H), 2.82 (s, 3H), 1.45 (s, 9H), 1.42(s, 9H). Mass spectrum (ESI, m/z): Calcd. for C₃₁H₃₉N₅O₆S₂ 642.3 (M+H),542.3 ((M-BOC)+H), 442.3 ((M-2 BOC)+H), found 642.0, 542.2, 442.3.

d)5-Methyl-4-{4-[3-(2-oxo-2-piperazinylethoxy)phenyl(1,3-thiazol-2-yl)}thiophene-2-carboxamidine:tert-Butyl4-(2-{3-[2-(5-{[(tert-butoxy)carbonylamino]iminomethyl}-2-methyl-3-thienyl)-1,3-thiazol-4-yl]phenoxy}acetyl)piperazinecarboxylate(25 mg, 0.039 mmol) treated with dichloromethane:trifluoroacetic acid1/1 (v:v) with 2.5% water added at room temperature for 2 h. Removal ofthe solvents in vacuo gave5-methyl-4-{4-[3-(2-oxo-2-piperazinylethoxy)phenyl](1,3-thiazol-2-yl)}thiophene-2-carboxamidine(27.4 mg, quantitive yield) as an off-white solid. ¹H-NMR (Methanol-d₄;300 MHz), δ 8.41 (s, 1H), 7.94 (s, 1H), 7.67 (m, 2H), 7.39 (m, 1H), 7.00(m, 1H), 4.96 (s, 2H), 3.88 (m, 4H), 3.25 (m, 4H), 2.95 (s, 3H). Massspectrum (ESI, m/z): Calcd. for C₂₁,H₂₃N₅O₂S₂ 442.1 (M+H), found 442.4.

EXAMPLE 152 Methyl 4-(2-bromoacetyl)-5-methylthiothiophene-2-carboxylate

To a stirring slurry of2-methylthio-(5-carbomethoxy)-thiophene-3-carboxylic acid (2.0 g, 8.61mmol) in 28 mL of CH₂Cl₂ under N₂ containing 0.8 mL DMF at 0° C. wasadded oxatyl chloride (1.9 equiv, 16.3 mmol) slowly via syringe. Thereaction was allowed to warm to ambient temperature after 1 h, and thenstirred an additional 1 h. The reaction mixture was filtered through a20 cm pad of silica gel in a 30 mL sintered glass funnel wetted with 50%ethyl acetate-hexanes and further eluted with the same solvent systemuntil the eluent showed no product by UV visualization. The solvent wasconcentrated in vacuo, azeotroped with toluene (1×), and dried undervacuum to afford the acid chloride (1.52 g) as a light yellow solid. Theacid chloride was dissolved in 20 mL of CH₁₃CN, cooled to 0° C., andtreated with TMSCHN₂ (2.1 equiv, 6.3 mL, 2 M in hexanes) dropwise viasyringe. The reaction was allowed to warm to ambient temperature (0.5h), cooled back to 5° C. and immediately treated with 30% HBr-aceticacid (0.66 mL) dropwise via an addition funnel. After 15 min. at 0° C.,the reaction diluted with 20 mL of ether, filtered and thoroughly washedwith ether (3×20 mL). The yellow solids were dried under vacuum toafford methyl 4-(2-bromoacetyl)-5-methylthiothiophene-2-carboxylate (1.0g, 37% yield) as a yellow powder. ¹H NMR (DMSO-d₆, 300 MHz) δ 2.66 (s,3H), 3.84 (s, 3H), 5.03 (s, 2H), 8.29 (s, 1H).

EXAMPLE 153 Isopropyl-4-(2-bromoacetyl)-5-methylthiophene-2-carboxylate

To a stirring slurry of2-methyl-(5-carboisopropoxy)-thiophene-3-carboxylic acid (0.40 g, 1.75mmol) in 15 mL of CH₂Cl₂ under N₂ containing 0.8 mL DMF at 0° C. wasadded oxalyl chloride (1.9 equiv, 3.32 mmol,) slowly via syringe. Thereaction was allowed to warm to ambient temperature after 1 h, and thenstirred an additional 1 h. The solvent was concentrated in vacuo,azeotroped with toluene (1×), and dried under vacuum to afford the acidchloride (0.397 g, 1.60 mmol) as a light yellow solid. The acid chloridewas dissolved in 7 mL of CH₃CN, cooled to 0° C., and treated withTMSCHN₂ (2.1 equiv, 1.68 mL, 2 M in hexanes) dropwise via syringe. Thereaction as allowed to warm to ambient temperature (0.5 h), cooled backto 5° C. and mmediately treated with 30% HBr-acetic acid (0.5 mL)dropwise via an addition funnel. After 15 min. at 0° C., the reactionmixture was filtered through a 10 cm pad of silica gel in a 15 mLsintered glass funnel wetted with 50% ethyl acetate-hexanes and furthereluted with the same solvent system until the eluent showed no productby UV visualization. The solvent was concentrated in vacuo dried undervacuum to affordisopropyl-4-(2-bromoacetyl)-5-methylthiophene-2-carboxylate (0.329 g,61% yield) as an oil which solidified upon standing to a tan solid. ¹HNMR (DMSO-d₆, 300 MHz) δ 1.31 (d, 6H, J=6.3 Hz), 2.71 (s, 3H), 4.60 (s,2H), 5.09 (m, 1H), 8.08 (s, 1H).

EXAMPLE 154

a) Methyl5-methylthio-4-[2-(phenylamino)-(1,3-thiazol-4-yl)]-thiophene-2-carboxylatehydrobromide: Methyl4-(2-bromoacetyl)-5-methylthiothiophene-2-carboxylate (60.5 mg, 0.19mmol) was slurried in 4 mL of acetone with phenyl thiourea (1 equiv, 30mg) and heated to 70° C. After 3 h the reaction was allowed to cool toroom temperature, filtered, and dried in vacuo to give 62.5 mg (69%yield) of methyl5-methylthio-4-[2-(phenylamino)-(1,3-thiazol-4-yl)]-thiophene-2-carboxylatehydrobromide. ¹H NMR (DMSO-d₆, 300 MHz) δ 2.65 (s, 3H), 3.83 (s, 3H),6.95-6.99 (m, 1H), 7.28-7.35 (m, 4H), 7.67 (d, 1H, J=1.4, 7.7 Hz), 8.06(s, 1H), 10.54 (s, 1H); Mass Spectrum (ESI) m/z calcd. for C₁₆H₁₄N₂O₂S₃,362.49 (M+H), found 363.7.

b)5-Methylthio-4-[2-(phenylamino)(1,3-thiazol-4-yl)]thiophene-2-carboxamidinehydrochloride: To a flame-dried flask containing 57.8 mg (8 equiv, 1.08mmol) of NH₄Cl under N₂ was charged 1.3 mL of toluene. AlMe₃ (8 equiv,2M/hexanes, 0.54 mL) was added dropwise to the stirred slurry over a 3min. period, and allowed to stir another 5 min. At this time methyl5-methylthio-4-[2-(phenylamino)-(1,3-thiazol-4-yl)]-thiophene-2-carboxylatehydrobromide (1 equiv, 60 mg, 0.135 mmol) was quickly added in oneportion and the resultant mixture was immersed in a 120° C. oil bath.After 2 h 10 min. at this temperature, TLC (silica gel 60 F₂₅₄, MerckKGaA, Darmstadt, Germany, 9:1:0.5 CH₂Cl₂—MeOH—AcOH eluent) indicated thereaction to be complete by disappearance of the starting material. Thereaction was allowed to cool to ambient temperature, then added viapipette to a stirred slurry of 1.3 g of SiO₂ in 20 mL of CHCl₃. Theresidual residue in the flask was rinsed with 4 mL of MeOH, brieflysonicated and added to the SiO₂ slurryl The slurry was stirred for 10min. and then filtered through a 15-mL sintered glass funnel containing20 cm of SiO₂ with 50% CHCl₃—MeOH. The yellow fraction was collected,discarding the forerun. TLC indicated the product was essentially pure.The solvent was removed in vacuo, and the residue triturated with 10%MeOH—CH₂Cl₂. The solids were removed by filtration. The solvent wasconcentrated in vacuo to give 30.1 mg (66% yield) of5-methylthio-4-[2-(phenylamino)-(1,3-thiazol-4-yl)]thiophene-2-carboxamidinehydrochloride as a red-brown powder. ¹H NMR (DMSO-d₆, 300 MHz) δ 2.73(s, 3H), 6.94-7.00 (m, 1H), 7.15 (s, 1H), 7.30-7.35 (m, 1H), 7.78 (d,1H, J=8.7 Hz), 8.49 (s, 1H), 8.87 (bs, 2H), 9.31 (bs, 2H), 10.38 (s,1H); Mass Spectrum (ESI) m/z calcd. for C₁₅H₁₄N₄S₃, 346.50 (M+H), found347.2.

EXAMPLE 155

a) Methyl4-{2-[(2-chlorophenyl)amino](1,3-thiazol-4-yl)}-5-methylthiothiophene-2-carboxylatehydrobromide: Methyl4-(2-bromoacetyl)-5-methylthiothiophene-2-carboxylate (50 mg) wasallowed to react with 2-chlorophenyl thiourea (26.7 mg) as described inExample 154, step (a), to give 58 mg (75%) of methyl4-{2-[(2-chlorophenyl)amino]-(1,3-thiazol-4-yl)}-5-methylthiothiophene-2-carboxylatehydrobromide. ¹H NMR (DMSO-d₆, 300 MHz) δ 2.66 (s, 3H), 3.82 (s, 3H),7.04 (m, 1H), 7.32-7.38 (m, 2H), 7.47 (dd, 1H, J=1.4,8.7 Hz), 8.12 (s,1H), 8.56 (dd, 1H, J=1.4, 8.3 Hz), 9.75 (s, 1H); Mass Spectrum (ESI) m/zcalcd. for C₁₆H₁₃CIN₂O₂S₃, 396.94 (M+H), found 397.1.

b)4-(2-[(2-Chlorophenyl)amino](1,3-tiazol-4-y)]-5-methylthiothiophene-2-carboxamidinehydrochloride: Methyl4-{2-[(2-chlorophenyl)amino]-(1,3-thiazol-4-yl)}-5-methylthiothiophene-2-carboxylatehydrobromide (40 mg, 0.08 mmol) was treated as described in Example 154,step (b) to give 24 mg (71.8%) of4-{2-[(2-chlorophenyl)amino]-(1,3-thiazol-4-yl)}-5-methylthiothiophene-2-carboxamidinehydrochloride. ¹H NMR (DMSO-d₆, 300 MHz) δ 2.71 (s, 3H), 7.04 (td, 1H,J=1.4, 7.8 Hz), 7.21 (s, 1H), 7.35 (t, 1H, J=8.5 Hz), 8.42 (s, 1H), 8.57(dd, 1H, J=1.3, 8.3 Hz), 8.80 (bs, 2H), 9.26 (bs, 2H), 9.79 (s, 1H);Mass Spectrum (ESI) m/z calcd. for C₁₅H₁₄N₄S₃Cl, 380.94 (M+H), found381.1.

EXAMPLE 156

a) Methyl4-(2-amino(1,3-thiazol-4-yl))-5-methylthiothiophene-2-carboxylatehydrobromide: Methyl4-(2-bromoacetyl)-5-methylthiothiophene-2-carboxylate (50 mg, 0.16 mmol)was allowed to react with thiourea (12 mg) as described in Example 154,step (a), to give 54 mg (70% yield) of methyl4-(2-amino-(1,3-thiazol-4-yl))-5-methylthiothiophene-2-carboxylatehydrobromide. ¹H NMR (DMSO-d₆, 300 MHz) δ 2.69 (s, 3H), 3.83 (s, 3H),7.00 (s, 1H), 8.05 (s, 1H); Mass Spectrum (ESI) m/z calcd. forC₁₀H₁₀O₂S₃N₂, 286.41 (M+H). found 287. 1;

b) 4-(2-Amino-(1,3-thiazol-4-yl))-5-methylthiothiophene-2-carboxamidinehydrochloride: Methyl4-(2-amino-(1,3-thiazol-4-yl))-5-methylthiothiophene-2-carboxylatehydrobromide (110 mg, 0;29 mmol) was treated as described in Example154, step (b). The resultant amidine (74 mg) was stirred in 3 mL of drymethanol under N₂ and treated with ca. 1 mL of ether saturated with dryHCl gas. Dry ether (1.5 mL) was then added and the result was allowed tosit for 2 h at ambient temperature and then filtered to give 40 mg (45%yield) of4-(2-amino-(1,3-thiazol-4-yl))-5-methylthiothiophene-2-carboxamidinehydrochloride. ¹H NMR (DMSO-d₆, 300 MHz) δ 2.69 (s, 3H), 6.90 (s, 1H),8.44 (s, 1H), 9.20, 9.42 (s, 4H, NH); Mass Spectrum (ESI) m/zcalcd.C₉H₁₀N₄S₃, 270.4 (M+H), found 271.2.

EXAMPLE 157

a) Methyl4-{2-[(2,5-dimethoxyphenyl)amino](1,3-thiazol-4-yl)}-5-methylthiothiophene-2-carboxylatehydrobromide: Methyl4-(2-bromoacetyl)-5-methylthiothiophene-2-carboxylate (49.4 mg, 0.15mmol) was allowed to react with 2,5-dimethoxy phenyl thiourea (37.2 mg)as described in Example 154, step (a), to give 65.5 mg (87% yield) ofmethyl4-{2-[(2,5-dimethoxyphenyl)amino](1,3-thiazol-4-yl)}-5-methylthiothiophene-2-carboxylatehydrobromide. ¹H NMR (DMSO-d₆, 300 MHz) δ 2.66 (s, 3H), 3.76 (s, 3H),3.81 (s, 3H), 3.83 (s, 3H), 6.49 (dd, 1H, J=3.0, 8.8 Hz), 6.92 (d, 1H,J=8.9 Hz), 7.26 (s, 1H), 8.17 (s, 1H), 8.37 (d, 1H, J=3.1 Hz), 9.70 (s,1H); Mass Spectrum (ESI) m/z calcd. for C₁₈H₁₈N₂O₄S₃, 422.54 (M+H),found 423. 1.

b)4-{2-[(2,5-Dimethoxyphenyl)amino](1,3-thiazol-4-yl)}-5-methylthiothiophene-2-carboxamidine:Methyl4-{2-[(2,5-dimethoxyphenyl)amino]-(1,3-thiazol-4-yl)}-5-methylthiothiophene-2-carboxylatehydrobromide (45.5 mg, 0.09 mmol) was treated as described in Example154, step b), followed by preparative thin layer chromatography (500 mmsilica gel plate, J. T. Baker, Phillipsburg, N.J.,10%-methanol-CH₂Cl₂-sat'd. NH₃ eluent) to give 9.9 mg 27% yield of4-{2-[(2,5-dimethoxyphenyl)amino](1,3-thiazol-4-yl)}-5-methylthiothiophene-2-carboxamidine.¹H NMR (DMSO-d₆, 300 MHz) δ 2.60 (s, 3H), 3.73 (s, 3H), 3.81 (s, 3H),6.48 (dd, 1H, J=3.1, 8.8 Hz), 6.92 (d, 1H, J=7.9 Hz), 7.05 (s, 1H), 7.5(bs, 2H), 8.04 (s, 1H), 8.34 (d, 1H, J=1.0 Hz), 9.6 (bs, 1H); MassSpectrum (ESI) m/z calcd. for C₁₇H₁₈N₄O₂S₃, 406.55 (M+H), found 407.1.

EXAMPLE 158

a) Methyl4-{2-[(3-methoxyphenyl)amino](1,3-thiazol-4-yl)}-5-methylthiothiophene-2-carboxylatehydrobromide: Methyl4-(2-bromoacetyl)-5-methylthiothiophene-2-carboxylate (53.3 mg, 0.17mmol) was allowed to react with 2-methoxy phenyl thiourea (34.5 mg) asdescribed in Example 154, step (a), to give 61 mg (76% yield) of methyl4-{2-[(3-methoxyphenyl)amino](1,3-thiazol-4-yl)}-5-methylthiothiophene-2-carboxylatehydrobromide. ¹H NMR (DMSO-d₆, 300 MHz) δ 62.67 (s, 3H), 3.78 (s, 3H),3.83 (s, 3H), 6.53 (d, 1H, J=6.8 Hz), 7.13-7.24 (m, 2H), 7.29 (s, 3H),7.59 (m, 1H), 8.16 (s, 3H), 10.32 (s, 1H); Mass Spectrum (ESI) m/zcalcd. for C₁₇H₁₆N₂O₃S₃, 392.52 (M+H), found 393.2.

b)4-{2-[(3-Methoxyphenyl)amino](1,3-thiazol-4-yl))-5-methylthiothiophene-2-carboxamidinehydrochloride: Methyl4-{2-[(3-methoxyphenyl)amino]-(1,3-thiazol-4-yl)}-5-methylthiothiophene-2-carboxylatehydrobromide (54.6 mg, 0.11 mmol) was treated as described in Example154, step (b) to give 25.2 mg (56%) of4-{2-[(3-methoxyphenyl)amino](1,3-thiazol-4-yl)}-5-methylthiothiophene-2-carboxamidinehydrochloride. ¹H NMR (DMSO-d₆, 300 MHz) δ 2.71 (s, 3H), 3.77 (s, 3H),6.54 (m, 1H), 7.15 (s, 3H), 7.19-7.28 (m, 2H), 7.47 (m, 1H), 8.46 (s,1H), 8.86 (bs, 2H), 9.28 (bs, 2H), 10.36 (s, 1H); Mass Spectrum (ESI)m/z calcd. for C₁₆H₁₆N₄OS₃, 376.52 (M+H), found 377.2.

EXAMPLE 159

a) Methyl4-(2-[(4-methoxyphenyl)amino](1,3-thiazol-4-yl)}-5-methylthiothiophene-2-carboxylatehydrobromide: Methyl4-(2-bromoacetyl)-5-methylthiothiophene-2-carboxylate (41.3 mg, 0.13mmol) was allowed to react with 5-methoxy phenyl thiourea (26.8 mg) asdescribed in Example 154, step (a) to give 25 mg (41% yield) of methyl4-{2-[(4-methoxyphenyl)amino](1,3-thiazol-4-yl)}-5-methylthiothiophene-2-carboxylatehydrobromide. ¹H NMR (DMSO-d₆, 300 MHz) δ 2.64, 2.68 (s, 3H rotomer)),3.72, 3.73 (s, 3H rotomer), 3.83 (s, 3H), 6.91 (dd, 2H, J=6.7, 8.8 Hz),7.21 (s, 1H), 7.59 (d, 1H, J=9.0 Hz), 7.67 (d, 1H, J=9.0 Hz), 8.05, 8.13(s, 1H rotomer), 10.16, 10.34 (bs, 1H, rotomer); Mass Spectrum (ESI) m/zcalcd. for C₁₇H₁₆N₂O₂S₃, 392.52 (M+H), found 393.1.

b)4-{2-[(4-Methoxyphenyl)amino](1,3-thriazol-4-yl)}-5-methyltdiothiophene-2-carboxamidinehydrochloride: Methyl4-{2-[(4-methoxyphenyl)amino]-(1,3-thiazol-4-yl)}-5-methylthiothiophene-2-carboxylatehydrobromide (22 mg, 0.046 mmol) was treated as described in Example154, step (b) to give 11.5 mg (61% yield) of4-{2-[(4-methoxyphenyl)amino](1,3-thiazol-4-yl)}-5-methylthiothiophene-2-carboxamidinehydrochloride. ¹H NMR (DMSO-d₆, 300 MHz) δ 2.72 (s, 3H), 3.73 (s, 3H),6.91 (d, 2H, J=9.0 Hz), 7.08 (s, 1H), 7.69 (d, 2H, J=9.1 Hz), 8.44 (s,1H), 8.83 (bs, 2H), 9.28 (bs, 2H), 10.15 (s, 1H);Mass Spectrum (ESI) m/zcalcd. for C₁₆H₁₆N₄OS₃, 376.52 (M+H), found 377.1.

EXAMPLE 160

a) Methyl4-(2-{[4-(dimethylamino)phenyl]amino}(1,3-thiazol-4-yl))-5-methylthiothiophene-2-carboxylatehIydrobromide: Methyl4-(2-bromoacetyl)-5-methylthiothiophene-2-carboxylate (50 mg, 0.16 mmol)was allowed to react with 4-N,N-dimethylaminophenyl thiourea (31.5 mg)as described in Example 154, step (a), to give 53.2 mg (75% yield) ofmethyl4-(2-{[4-(dimethylamino)phenyl]amino}(1,3-thiazol-4-yl))-5-methylthiothiophene-2-carboxylatehydrobromide. ¹H NMR (DMSO-d₆, 300 MHz) δ 2.69 (s, 3H), 3.15 (s, 6H),3.83 (s, 3H), 7.36 (s, 1H), 7.55 (bs, 2H), 7.88 (d, 2H, J=8.3 Hz), 8.16(s, 1H), 10.56 (bs, 1H); Mass Spectrum (ESI) m/z calcd. forC₁₈H₁₉N₃O₂S₃, 405.56 (M+H), found 406.1.

b)4-(2-{[4-(Dimethylamino)phenyl]amino}(1,3-thiazol-4-yl))-5-methylthiothiophene-2-carboxamidinehydrochloride: Methyl4-(2-{([4-(dimethylamino)phenyl]amino}(1,3-thiazol-4-yl))-5-methylthiothiophene-2-carboxylatehydrobromide (50 mg, 0.10 mmol) was treated as described in Example 154,step (b) to give 9.4 mg (22% yield) of4-{2-[(4-methoxyphenyl)amino](1,3-thiazol-4-yl)}-5-methylthiothiophene-2-carboxamidinehydrochloride. ¹H NMR (DMSO-d₆, 300 MHz) 2.70 (s, 3H), 2.84 (s, 6H),6.75 (d, 2H, J=9.2 Hz), 7.00 (s, 1H), 7.56 (d, 2H, J=9.1 Hz), 8.31 (s,1H), 8.68 (bs, 3H), 9.92 (bs, 1H).

EXAMPLE 161

a) Methyl4-{2-[(4-chloro-2-methylphenyl)amino](1,3-thiazol-4-yl)}-5-methylthiothiophene-2-carboxylatehydrobromide: Methyl4-(2-bromoacetyl)-5-methylthiothiophene-2-carboxylate (50 mg, 0.16 mmol)was allowed to react with 2-methyl-4-chlorophenyl thiourea (32.1 mg) asdescribed in Example 154, step (a), to give 62.2 mg (79% yield) ofmethyl4-{2-[(4-chloro-2-methylphenyl)amino](1,3-thiazol-4-yl)}-5-methylthiothiophene-2-carboxylatehydrobromide. ¹H NMR (DMSO-d₆, 300 MHz) δ 2.28, 2.29 (s, 3H rotomer),2.62, 2.66 (s, 3H rotomer), 3.82 (s, 1H), 7.21-7.29 (m, 3H), 8.04, 8.11(s, 1H rotomer), 8.17 (d, 1H, J=8.8 Hz), 8.30 (d, 1H, J=8.4 Hz), 9.44(s, 1H), 9.59 (s, 1H); Mass Spectrum (ESI) m/z calcd. forC₁₇H₁₅ClN₂O₂S₃, 410.96 (M+H), found 411.1.

b)4-{2-[(4-Chloro-2-methylphenyl)amino](1,3-thiazol-4-yl)}-5-methylthiothiophene-2-carboxamidinehydrochloride: Methyl4-{2-[(4-chloro-2-methylphenyl)amino]-(1,3-thiazol-4-yl)}-5-methylthiothiophene-2-carboxylatehydrobromide (55 mg, 0.17 mmol) was treated as described in Example 154,step (b) to give 16 mg (22% yield) of4-{2-[(4-chloro-2-methylphenyl)amino](1,3-thiazol-4-yl)}-5-methylthiothiophene-2-carboxamidinehydrochloride. ¹H NMR (DMSO-d₆, 300 MHz) δ 2.30 (s, 3H), 2.70 (s, 3H),7.15 (s, 1H), 7.23-7.29 (m, 2H), 8.34 (d, 1H, J=8.6 Hz), 8.44 (s, 1H),8.86 (bs, 2H), 9.29 (bs, 2H), 9.47 (s, 1H); Mass Spectrum (ESI) m/zcalcd. for C₁₆H₁₅ClN₄S₃, 394.97 (M+H), found 395.1.

EXAMPLE 162

a) Methyl4-{2-[(diphenylmethyl)amino](1,3-thiazol-4-yl)}-5-methylthiothiophene-2-carboxylatehydrobromide: Methyl4-(2-bromoacetyl)-5-methylthiothiophene-2-carboxylate (50 mg, 0.16 mmol)was allowed to react with diphenylmethane thiourea (38 mg) as describedin Example 154, step (a), to give 145 mg (100% yield) of methyl4-{2-[(diphenylmethyl)amino](1,3-thiazol-4-yl)}-5-methylthiothiophene-2-carboxylatehydrobromide after removal of solvent in vacuo. ¹H NMR (DMSO-d₆, 300MHz) δ 2.50 (s, 3H), 2.80 (s, 3H), 6.13, 6.18 (d, 1H rotomer, J=7.9 Hz),7.23-7.41 (m, 11H), 8.00, 8.02 (s, 1H rotomer), 8.73, 8.86 (d, 1H,rotomer, J=8.0 Hz); Mass Spectrum (ESI) m/z calcd. for C₂₃H₂₀N₂O₂S₃,452.62 (M+H), found 453.0.

b)4-{2[(Diphenylmethyl)amino](1,3-thiazol-4-yl)}-5-methylthiothiophene-2-carboxamidine:Methyl4-{2-[(diphenylmethyl)amino](1,3-thiazol-4-yl)}-5-methylthiothiophene-2-carboxylatehydrobromide. (96.3 mg. 0.18 mmol) was treated as described in Example154, step (b) to give 16 mg (20% yield) of4-{2-[(diphenylmethyl)amino](1,3-thiazol-4-yl)}-5-methylthiothiophene-2-carboxamidinehydrochloride. ¹H NMR (DMSO-d₆, 300 MHz) 2.59 (s, 3H), 6.23 (d, 1H,J=7.9 Hz), 6.84 (s, 1H), 7.22-7.40 (m, 10 H), 8.09 (bs, 3H), 8.12 (s,1H), 8.68 (d, 1H, J=8.4 Hz); Mass Spectrum (ESI) m/z calcd. forC₂₂H₂₀N₄S₃, 436.62 (M+H), found 437.1.

EXAMPLE 163

a) Methyl5-methylthio-4-{2-[(3-phenylpropyl)amino](1,3-tlhiazol-4-yl}thiophene-2-carboxylatehydrobromide: Methyl4-(2-bromoacetyl)-5-methylthiothiophene-2-carboxylate (131 mg, 0.42mmol) was allowed to react with propylphenyl thiourea (82.3 mg) in DMFas described in Example 154, step (a), then filtered through a 5 cm padof silica gel in a 15 mL glass fritted funnel with 10% methanol-CHCl₃.Concentration of the solvent in vacuo gave 203 mg (100% yield) of methyl5-methylthio-4-{2-[(3-phenylpropyl)amino](1,3-thiazol-4-yl)}thiophene-2-carboxylatehydrobromide. ¹H NMR (DMSO-d₆, 300 MHz) δ 1.89 (m, 2H), 2.62 (s, 3H),2.63-2.71 (m, 2H), 3.27-3.39 (m, 2H), 3.82 (s, 3H), 6.97 (s, 1H),7.15-7.31 (m, 5H), 8.06 (s, 1H); Mass Spectrum (ESI) mn/z calcd. forC₁₉H₂₀N₂O₂S₃, 404.57 (M+H), found 405.1.

b)5-Methylthio-4-{2[(3-phenylpropyl)amino](1,3-thiazol-4-yl)}thiophene-2-carboxamidinehydrochloride:Methyl-5-methylthio-4-{2-[(3-phenylpropyl)amino](1,3-thiazol-4-yl)}thiophene-2-carboxylatehydrobromide (112 mg, 0.23 mmol) was treated as described in Example154, step (b) to give 16 mg (16% yield) of4-{2-[(diphenylmethyl)amino](1,3-thiazol-4-yl)}-5-methylthiothiophene-2-carboxamidinehydrochloride, which was further purified by preparative thin layerchromatography using 20%-methanol-CH₂Cl₂-sat'd. NH₃ as eluent. ¹H NMR(DMSO-d₆, 300 MHz) δ 1.89 (m, 2H), 2.54 (s, 1H), 2.66 (at, 2H, J=7.3Hz), 3.31 (m, 2H), 6.69 (bs, 3H), 6.76 (s, 1H), 7.15-7.31 (m, 5H), 7.69(m, 1H), 7.84 (s, 1H); Mass Spectrum (ESI) m/z calcd. for C₁₈H₂₀N₄S₃,388.58 (M+H), found 389.2.

EXAMPLE 164

a) Methyl5-methylthio-4-{2-[(2,4,5-trimethylphenyl)amino](1,3-thiazol-4-yl)}thiophene-2-carboxylatehydrobromide: Methyl4-(2-bromoacetyl)-5-methylthiothiophene-2-carboxylate (60 mg, 0.21 mmol)was allowed to react with 2,4,5-trimethylphenyl thiourea as described inExample 154, step (a) to give 42.3 mg (41% yield) of methyl5-methylthio-4-{2-[(2,4,5-trimethylphenyl)amino](1,3-thiazol-4-yl)}thiophene-2-carboxylatehydrobromide. ¹H NMR (DMSO-d₆, 300 MHz) δ 2.16 (s, 3H), 2.18 (s, 3H),2.19 (s, 3H), 2.64 (s, 3H), 3.82 (s, 3H), 6.97 (s, 1H), 7.18 (s, 1H),7.86 (s, 1H), 8.12 (s, 1H), 9.29 (s, 1H); Mass Spectrum (ESI) m/z calcd.for C₁₉H₂₀N₂O₂S₃, 404.57 (M+H), found 405.1.

b)5-Methylthio-4-{2-[(2,4,5-trimethyphenyl)amino](1,3-thiazol-4-yl)]}thiophene-2-carboxamidinehydrochloride:Methyl-5-methylthio-4-}2-[(2,4,5-trimethylphenyl)amino](1,3-thiazol-4-yl)}thiophene-2-carboxylatehydrobromide (37.3 mg, 0.07 mmol) was treated as described in Example154, step (b) to give 28.3 mg (95% yield) of5-methylthio-4-{2-[(2,4,5-trimethylphenyl)amino](1,3-thiazol-4-yl)}thiophene-2-carboxamidinehydrochloride. ¹H NMR (DMSO-d₆, 300 MHz) δ 2.16 (s, 3H), 2.19 (s, 3H),2.20 (s, 3H), 2.68 (s, 3H), 6.97 (s, 1H), 7.03 (s, 1H), 7.84 (s, 1H),8.41 (s, 1H), 8.84 (bs, 2H), 9.26 (bs, 3H); Mass Spectrum (ESI) m/zcalcd. for C₁₈H₂₀N₄S₃, 388.58 (M+H), found 389.2.

EXAMPLE 165

a) Methyl4-{2-[(2-fluorophenyl)amino](1,3-thiazol-4-yl)}-5-methylthiothiophene-2-carboxylatehydrobromide: Methyl4-(2-bromoacetyl)-5-methylthiothiophene-2-carboxylate (60 mg, 0.19 mmol)was allowed to react with 2-fluorophenyl thiourea as described inExample 154, step (a) to give 55.6 mg (70% yield) of methyl4-{2-[(2-fluorophenyl)amino](1,3-thiazol-4-yl)}-5-methylthiothiophene-2-carboxylatehydrobromide. ¹H NMR (DMSO-d₆, 300 MHz) δ 2.68 (s, 3H), 3.83 (s, 3H),6.96-7.04 (m, 1H), 7.14-7.29 (m, 3H), 7.35 (s, 1H), 8.06, 8.14 (s, 1Hrotomer), 8.61 (td, 1H rotomer, J=1.5, 8.5 Hz), 10.14, 10.30 (s, 1Hrotomer); Mass Spectrum (ESI) m/z calcd. for C₁₆H₁₃FN₂O₂S₃, 380.48(M+H), found 381.1.

b)4-{2-[(2-Fluorophenyl)amino](1,3-thiazol-4-yl)}-5-methylthiothiophene-2-carboxamidinehydrochloride: Methyl4-{2-[(2-fluorophenyl)amino](1,3-thiazol-4-yl)}-5-methylthiothiophene-2-carboxylatehydrobromide (55.6 mg, 0.13 mmol)) was treated as described in Example154, step (b) to give 12.4 mg (24%) of4-{2-[(2-fluorophenyl)amino](1,3-thiazol-4-yl)}-5-methylthiothiophene-2-carboxamidinehydrochloride. ¹H NMR (DMSO-d₆, 300 MHz); δ 2.72 (s, 3H), 3.16 (s, 3H),6.97-7.08 (m, 1H), 7.18-7.36 (m, 4H), 8.49 (s, 1H), 8.70 (td, 1H, 1.4,8.4 Hz), 8.92 (bs, 2H), 9.32 (bs, 2H), 10.18 (d, 1H, J=1.6 Hz); MassSpectrum (ESI) m/z calcd. for C₁₅H₁₃FN₄S₃, 364.49 (M+H), found 365.1.

EXAMPLE 166

a) Methyl4-{2-[(3-chloro-2-methylphenyl)amino](1,3-thiazol-4-yl)}-5-methylthiothiophene-2-carboxylatehydrobromide: Methyl4-(2-bromoacetyl)-5-methylthiothiophene-2-carboxylate (60 mg, 0.19 mmol)was allowed to react with 2-methyl-3-chlorophenyl thiourea (39 mg) asdescribed in Example 154, step (a) to give 61.8 mg (66% yield) of methyl4-{2-[(3-chloro-2-methylphenyl)amino](1,3-thiazol-4-yl)}-5-methylthiothiophene-2-carboxylatehydrobromide. Mass Spectrum (ESI) m/z calcd. for C₁₇H₁₅ClN₂O₂S₃, 410.96(M+H), found 411.1.

b)4-{2-[(3-Chloro-2-methylphenyl)amino](1,3-thiazol-4-yl)}-5-methylthiothiophene-2-carboxamidinehydrochloride: Methyl4-{2-[(3-chloro-2-methylphenyl)amino](1,3-thiazol-4-yl)}-5-methylthiothiophene-2-carboxylatehydrobromide (61.8 mg, 0.12 mmol) was treated as described in Example154, step (b) to give 46.7 mg (90% yield) of4-{2-[(3-chloro-2-methylphenyl)amino](1,3-thiazol-4-yl)}-5-methylthiothiophene-2-carboxamidinehydrochloride. ¹H NMR (DMSO-d₆, 300 MHz) δ 2.34 (s, 3H), 2.69 (s, 3H),7.15 (s, 1H), 7.18-7.26 (m, 2H), 8.12 (d, 1H, J=7.9 Hz), 8.41 (s, 1H),8.84 (bs, 2H), 9.27 (bs, 2H), 9.61 (s, 1H); Mass Spectrum (ESI) m/zcalcd. for C₁₆H₁₅ClN₄S₃, 394.97 (M+H), found 395.1.

EXAMPLE 167

a) Methyl4-(2-{[2-(methylethyl)phenyl]amino}(1,3-thiazol-4-yl))-5-methylthiothiophene-2-carboxylatehydrobromide: Methyl4-(2-bromoacetyl)-5-methylthiothiophene-2-carboxylate (60 mg, 0.19 mmol)was allowed to react with 2-isopropyl phenyl thiourea (40 mg) asdescribed in Example 154, step (a) to give 33.1 mg (36% yield) of methyl4-(2-{[2-(methylethyl)phenyl]amino}(1,3-thiazol-4-yl))-5-methylthiothiophene-2-carboxylatehydrobromide. ¹H NMR (DMSO-d₆, 300 MHz) δ 1.17 (d, 6H, J=6.7 Hz), 2.60,2.65 (s, 3H rotomer), 3.27 (s, 1H), 3.82 (s, 3H), 7.13 (s, 1H),7.14-7.25 (m, 2H), 7.34-7.37 (m, 1H), 7.78 (m, 1H), 7.99, 8.08 (s, 1Hrotomer), 9.52, 9.61 (bs, 1H rotomer); Mass Spectrum (ESI) m/z calcd.for C₁₉H₂₀N₂O₂S₃, 404.57 (M+H), found 405.1.

b)4-(2-{[2-(Methylethyl)phenyl]amino}(1,3-thiazol-4-yl))-5-methylthiothiophene-2-carboxamidinehydrochloride: Methyl4-(2-{[2-(methylethyl)phenyl]amino}(1,3-thiazol-4-yl))-5-methylthiothiophene-2-carboxylatehydrobromide (33.1 mg, 0.06 mmol) was treated as described in Example154, step (b) to give 22.4 mg (88%) of4-(2-{[2-(methylethyl)phenyl]amino}(1,3-thiazol-4-yl))-5-methylthiothiophene-2-carboxamidinehydrochloride. ¹H NMR (DMSO-d₆, 300 MHz) δ 1.19 (d, 6H, J=6.8 Hz), 2.70(s, 3H), 3.32 (m, 1H), 7.04 (s, 1H), 7.14-7.25 (m, 2H), 7.35 (dd, 1H,J=1.4, 7.5 Hz), 7.86 (dd, 1H, J=1.4, 7.9 Hz), 8.37 (s, 1H); MassSpectrum (ESI) m/z calcd. for C₁₈H₂₀N₄S₃, 388.58 (M+H), found 389.2.

EXAMPLE 168

a) Methyl5-methylthio-4-(2-{[4-(phenylmethoxy)phenyl]amino}(1,3-thiazol-4-yl))thiophene-2-carboxylate:Methyl 4-(2-bromoacetyl)-5-methylthiothiophene-2-carboxylate (336.3 mg,1.08 mmol) was allowed to react with 4-benzyloxyphenyl thiourea (279 mg)as described in Example 154, step (a) to give 450 mg (76% yield) ofmethyl4-(2-{[4-phenylmethoxyphenyl]amino}(1,3-thiazol-4-yl))-5-methylthiothiophene-2-carboxylatehydrobromide. Mass Spectrum (ESI) m/z calcd. for C₂₃H₂₀N₂O₃S₃, 468.61(M+H), found 469.2.

b)5-Methylthio-4-(2-{[4-(phenylmethoxy)phenyl]amino}(1,3-thiazol-4-yl))thiophene-2-carboxamidinehydrochloride: Methyl4-(2-{[4-phenylmethoxyphenyl]amino}(1,3-thiazol-4-yl))-5-methylthiothiophene-2-carboxylatehydrobromide (100 mg, 0.18 mmol) was treated as described in Example154, step (b) to give 23.9 mg (27% yield)5-methylthio-4-(2-{[4-(phenylmethoxy)phenyl]amino}(1,3-thiazol-4-yl))thiophene-2-carboxamidinehydrochloride. ¹H NMR (DMSO-d₆, 300 MHz) δ 2.73 (s, 3H), 5.08 (s, 2H),7.00 (d, 2H, J=8.2 Hz), 7.09 (s, 1H), 7.31-7.47 (m, 5H), 7.70 (d, 2H,J=8.0 Hz), 8.47 (s, 1H), 8.88 (bs, 2H), 9.30 (bs, 2H), 10.20 (s, 1H);Mass Spectrum (ESI) m/z calcd. for C₂₂H₂₀N₄OS₃, 452.62 (M+H), found453.1.

EXAMPLE 169

a) Methyl4-{2-[(2-bromophenyl)amino](1,3-thiazol-4-yl)}-5-methylthiothiophene-2-carboxylatehydrobromide: Methyl4-(2-bromoacetyl)-5-methylthiothiophene-2-carboxylate (60 mg, 0.19 mmol)was allowed to react with 2-bromophenyl thiourea (44 mg) as described inExample 154, step (a) to give 63.1 mg (64% yield) of methyl4-{2-[(2-bromophenyl)amino](1,3-thiazol-4-yl)}-5-methylthiothiophene-2-carboxylatehydrobromide. ¹H NMR (DMSO-d₆, 300 MHz) δ 2.65 (s, 3H), 3.82 (s, 3H),7.00 (m, 1H), 7.33 (s, 1H), 7.40 (m, 1H), 7.64 (dd, 1H, J=1.4, 7.9 Hz),8.04, 8.11 (s, 1H rotomer), 8.27, 8.37 (dd, 1H 9.60, 9.80 (bs, 1Hrotomer, J=1.5, 8.2 Hz), Mass Spectrum (ESI) m/z calcd. forC₁₆H₁₃BrN₂O₂S3, 441.39 (M+H), found 441.1.

b)4-{2-[(2-Bromophenyl)amino](1,3-thiazol-4-yl)}-5-methylthiothiophene-2-carboxamidinehydrochloride: Methyl4-{2-[(2-bromophenyl)amino](1,3-thiazol-4-yl)}-5-methylthiothiophene-2-carboxylatehydrobromide (63.1 mg, 0.12 mmol) was treated as described in Example154, step (b) to give 47.9 mg (86% yield) of4-{2-[(2-bromophenyl)amino](1,3-thiazol-4-yl)}-5-methylthiothiophene-2-carboxamidinehydrochloride. ¹H NMR (DMSO-d₆, 300 MHz) δ 2.70 (s, 3H), 7.01 (m 1H),7.20 (s, 1H), 7.40 (m, 1H), 7.65 (dd, 1H, J=1.5, 8.0), 8.38 (dd, 1H,J=1.5, 8.3 Hz), 8.44 (s, 1H), 8.89 (bs, 2H), 9.30 (bs, 2H), 9.62 (s,1H); Mass Spectrum (ESI) m/z calcd. for C₁₅H₁₃BrN₄S₃, 425.39 (M+H),found 425.1.

EXAMPLE 170

a) Methyl4-{2-[(2,6-dichlorophenyl)amino](1,3-thiazol-4-yl)}-5-methylthiothiophene-2-carboxylatehydrobromide: Methyl4-(2-bromoacetyl)-5-methylthiothiophene-2-carboxylate (60 mg, 0.19 mmol)was allowed to react with 2,6-dichlorophenyl thiourea (42 mg) asdescribed in Example 154, step (a) to give 63.1 mg (65% yield) of methyl4-{2-[(2,6-dichlorophenyl)amino](1,3-thiazol-4-yl)}-5-methylthiothiophene-2-carboxylatehydrobromide. ¹H NMR (DMSO-d₆, 300 MHz) δ 2.59 (s, 3H), 3.8 (s, 3H),7.15 (s, 1H), 7.36 (m, 11), 7.61 (m, 2H), 7.97 (s, 1H); Mass Spectrum(ESI) m/z calcd. for C₁₆H₁₂Cl₂N₂O₂S₃, 431.38 (M+H), found 431.0.

b)4-{2-[(2,6-Dichlorophenyl)amino](1,3-thiazol-4-yl)}-5-methylthiothiophene-2-carboxamidinehydrochloride: Methyl4-{2-[(2,6-dichlorophenyl)amino](1,3-thiazol-4-yl)}-5-methylthiothiophene-2-carboxylatehydrobromide (43 mg, 0.08 mmol) was treated as described in Example 154,step (b) to give 14.5 mg (40% yield) of4-{2-[(2,6-dichlorophenyl)amino](1,3-thiazol-4-yl)}-5-methylthiothiophene-2-carboxamidinehydrochloride. ¹H NMR (DMSO-d₆, 300 MHz) δ 2.69 (s, 3H), 7.15 (s, 1H),7.18-7.26 (m, 2H), 8.13 (d, 1H, J=7.5 Hz), 8.41 (s, 1H), 8.84 (bs, 2H),9.27 (bs, 2H), 9.61 (bs, 1H); Mass Spectrum (ESI) m/z calcd. forC₁₅H₁₂Cl₂N₄S₃, 415.39 (M+H), found 415.1.

EXAMPLE 171

a) Methyl4-{2-[(2-bromo-4-methylphenyl)amino](1,3-thiazol-4-yl)}-5-methylthiothiophene-2-carboxylatehydrobromide: Methyl4-(2-bromoacetyl)-5-methylthiothiophene-2-carboxylate (60 mg, 0.19 mmol)was allowed to react with 2-bromo-4-methylphenyl thiourea (47 mg) asdescribed in Example 154, step (a) to give 62 mg (61% yield) of methyl4-{2-[(2-bromo-4-methylphenyl)amino](1,3-thiazol-4-yl)}-5-methylthiothiophene-2-carboxylatehydrobromide. ¹H NMR (DMSO-d₆, 300 MHz) δ 2.28 (s, 3H), 3.82 (s, 3H),7.21 (m, 1H), 7.27 (s, 1H), 7.48 (m, 1H), 8.14, 8.17 (s, 1H rotomer),9.52, 9.72 (bs, 1H rotomer); Mass Spectrum (ESI) m/z calcd. forC₁₇H₁₅BrN₂O₂S₃, 455.42 (M+H), found 455.0.

b)4-{2-[(2-Bromo4-methylphenyl)amino](1,3-thiazol-4-yl)}-5-methylthiothiophene-2-carboxamidinehydrochloride: Methyl4-{2-[(2-bromo-4-methylpheny)amino](1,3-thiazol-4yl)}-5-methylthiothiophene-2-carboxylatehydrobromide (62 mg, 0. 11 mmol) was treated as described in Example154, step (b) to give 26 mg (50% yield) of4-{2-[(2-bromo-4-methylphenyl)amino](1,3-thiazol-4-yl)}-5-methylthiothiophene-2-carboxamidinehydrochloride. ¹H NMR (DMSO-d₆, 300 MHz) δ 2.28 (s, 3H), 2.70 (s, 3H),7.14 (s, 1H), 7.21 (dd, 1H, J=1.6, 8.5 Hz), 7.49 (d, 1H, J=1.5 Hz), 8.16(d, 1H, 8.3 Hz), 8.41 (s, 1H), 8.85 (bs, 2H), 9.28 (bs, 2H), 9.53 (s,1H); Mass Spectrum (ESI) m/z calcd. for C₁₆H₁₅BrN₄S₃, 439.42 (M+H),found 439.1.

EXAMPLE 172

a) Methyl5-methylthio-4-{2-[(2-morpholin-4-ylethyl)amino](1,3-thiazol-4-yl)}thiophene-2-carboxylatehydrobromide: Methyl4-(2-bromoacetyl)-5-methylthiothiophene-2-carboxylate (100 mg, 0.32mmol), was allowed to react with 1-ethylmorpholinothiourea (61.2 mg) asdescribed in Example 154, step (a) to give 120.8 mg (79% yield) methyl5-methylthio-4-{2-[(2-morpholin-4-ylethyl)amino](1,3-thiazol-4-yl)}thiophene-2-carboxylatehydrobromide. ¹H NMR (CD₃OD, 300 MHz) δ 2.64 (s, 3H), 3.43-3.52 (m, 5H),3.83-3.86 (m, 10H), 6.95 (s, 1H), 8.04 (s, 1H); Mass Spectrum (ESI) m/zcalcd. for C₁₆H₂₁N₃O₃S₃, 399.55 (M+H), found 400.1.

b)5-Methylthio-4-{2-[(2-morpholin-4-ylethyl)amino](1,3-thiazol-4-yl)}thiophene-2-carboxylatehydrochloride:Methyl-5-methylthio-4-{2-[(2-morpholin-4-ylethyl)amino](1,3-thiazol-4-yl)}thiophene-2-carboxylatehydrobromide (62 mg, 0.12 mmol) was treated as described in Example 154,step (b) to give 26 mg (52% yield) of5-methylthio-4-{2-[(2-morpholin-4-ylethyl)amino](1,3-thiazol-4-yl)}thiophene-2-carboxylatehydrochloride. ¹H NMR (DMSO-d₆, 300 MHz) δ 2.69 (s, 3H), 3.16-3.95 (m,15H), 6.96 (s, 1H), 8.01 (bs, 1H), 8.49 (s, 1H), 8.84 (bs, 2H), 9.28(bs, 2H), 10.49 (bs, 1H); Mass Spectrum (ESI) m/z calcd. forC₁₅H₂₁N₅OS₃, 383.56 (M+H), found 384.2.

EXAMPLE 173

a) Methyl4-{2-[(2,3-dichlorophenyl)amino](1,3-thiazol-4-yl)}-5-methylthiothiophene-2-carboxylatehydrobromide: Methyl4-(2-bromoacetyl)-5-methylthiothiophene-2-carboxylate (60 mg, 0.19 mmol)was allowed to react with 2,3-dichlorophenylthiourea (42 mg) asdescribed in Example 154, step (a) to give 60.5 mg (62% yield) methyl4-{2-[(2,3-dichlorophenyl)amino](1,3-thiazol-4-yl)}-5-methylthiothiophene-2-carboxylatehydrobromide. ¹H NMR (DMSO-d₆, 300 MHz) δ 2.66 (s, 3H), 3.82 (s, 3H),7.27 (dd, 1H, J=1.5, 6.5 Hz), 7.36 (d, 1H, J=8.2 Hz), 7.43 5 (s, 1H),8.14 (s, 1H), 8.62 (dd, 1H, J=1.5, 8.4 Hz), 9.95 (bs, 1H); Mass Spectrum(ESI) m/z calcd. for C₁₆H₁₂Cl₂N₂O₂S₃, 431.38 (M+H), found 431.1.

b)4-{2-[(2,3-Dichlorophenyl)amino](1,3-thiazol-4-yl)}-5-methylthiothiophene-2-carboxamidinehydrochloride: Methyl4-{2-[(2,3-dichlorophenyl)amino](1,3-thiazol-4-yl)}-5-methylthiothiophene-2-carboxylatehydrobromide (60.5 mg, 0.11 mmol) was treated as described in Example154, step (b) to give 15 mg (30% yield) of4-{2-[(2,3-dichlorophenyl)amino](1,3-thiazol-4-yl)}-5-methylthiothiophene-2-carboxamidinehydrochloride. ¹H NMR (DMSO-d₆, 300 MHz) δ 2.71 (s, 3H), 7.27-7.28-7.41(m, 2H), 8.45 (s, 1H), 8.63 (dd, 1H, J=1 .5, 8.4 Hz), 8.84 (bs, 2H),9.29 (bs, 2H), 9.99 (s, 1H); Mass Spectrum (ESI) m/z calcd. forC₁₅H₁₂Cl₂N₄S₃, 415.34 (M+H), found 415.1.

EXAMPLE 174

a) Methyl5-metltylthio-4-{2-[(3,4,5-trimethoxyphenyl)amino](1,3-thiazol-4-yl)}thiophene-2-carboxylatehydrobromide: Methyl 4-(2-bromoacetyl)-5-20methylthiothiophene-2-carboxylate (60 mg, 0.19 mmol) was allowed toreact with 2,3,4-trimethoxyphenylthiourea (46 mg) as described inExample 154, step (a) to give 61.8 mg (63% yield) of methyl5-methylthio-4-{2-[(3,4,5-trimethoxyphenyl)amino](1,3-thiazol-4-yl)}thiophene-2-carboxylatehydrobromide. ¹H NMR (DMSO-d₆, 300 MHz) δ 2.67 (s, 3H), 3.81 (s, 6H),3.82 (s, 3H), 7.11 (s, 2H), 7.25 (s, 1H), 8.19 (s, 1H), 10.25 (s, 1H);Mass Spectrum (ESI) m/z calcd. for C₁₈H₂₀N₄O₃S₃, 436.56 (M+H), found437.1.

b)5-Methylthio-4-{2-[(3,4,5-trimethoxyphenyl)amino](1,3-thiazol-4-yl)}thiophene-2-carboxamidinehydrochloride: Methyl5-methylthio-4-{2-[(3,4,5-trimethoxyphenyl)amino](1,3-thiazol-4-yl)}thiophene-2-carboxylatehydrobromide (61.8 mg, 0.11 mmol) was treated as described in Example154, step (b) to give 14 mg (27% yield) of5-methylthio-4-{2-[(3,4,5-trimethoxyphenyl)amino](1,3-thiazol-4-yl)}thiophene-2-carboxamidinehydrochloride. ¹H NMR (DMSO-d₆, 300 MHz) δ 2.70 (s, 3H), 3.61 (s, 3H),3.80 (s, 6H), 7.08 (s, 2H), 7.14 (s, 1H), 8.44 (s, 1H), 8.84 (bs, 2H),9.26 (bs, 2H), 10.29 (s, 1 H); Mass Spectrum (ESI) m/z calcd. forC₁₈H₂₀N₄O₃S₃, 436.56 (M+H), found 437.1.

EXAMPLE 175

a) Methyl5-methylthio-4-{2-[(2-piperidylethyl)amino](1,3-thiazol-4-yl)}thiophene-2-carboxylatehydrobromide: Methyl4-(2-bromoacetyl)-5-methylthiothiophene-2-carboxylate (100 mg, 0.32mmol) was allowed to react with N-ethylpiperidylthiourea (60.6 mg) asdescribed in Example 154, step (a) to give 90 mg (59% yield) of methyl5-methylthio-4-{2-[(2-piperidylethyl)amino](1,3-thiazol-4-yl)}thiophene-2-carboxylatehydrobromide. ¹H NMR (DMSO-d₆, 300 MHz) δ 1.41 (m, 2H), 1.70-1.79 (m,6H), 2.65 (s, 3H), 2.95 (m, 2H), 3.52 (m, 2H), 3.73 (m, 2H),3.82 (s,3H), 7.08 (s, 1H), 7.96 (at, 1H, J=5.3 Hz), 8.09 (s, 1H), 9.40 (bs, 1H);Mass Spectrum (ESI) m/z calcd. for C₁₇H₂₃N₃O₂S₃, 397.6 (M+H), found398.1.

b)5-Methylthio-4-{2-[(2-piperidylethyl)amino](1,3-thiazol-4-yl)}thiophene-2-carboxamidinehydrochloride: Methyl5-methylthio-4-{2-[(2-piperidylethyl)amino](1,3-thiazol-4-yl)}thiophene-2-carboxylatehydrobromide (72 mg, 0.15 mmol) was treated as described in Example 154,step (b) to give 26.8 mg (43% yield) of5-methylthio-4-{2-[(2-piperidylethyl)amino](1,3-thiazol-4-yl)}thiophene-2-carboxamidinehydrochloride. ¹H NMR (DMSO-d₆, 300 MHz) δ 1.40 (m, 2H), 1.72-1.79 (m,6H), 2.69 (s, 3H), 2.96 (m, 2H), 3.5I (m, 2H), 3.76 (m, 2H), 6.97 (s,1H), 8.08 (t, 1H, J=S.5 Hz), 8.60 (s, 1H), 8.95 (bs, 1H), 9.35 (bs, 2H),10.25 (s, 1H); Mass Spectrum (ESI) m/z calcd. for C₁₆H₂₃N₅S₃, 381.1(M+H), found 382.2.

EXAMPLE 176

a) Methyl4-(2-{[(4-methylphenyl)methyl]amino}(1,3-thiazol-4-yl))-5-methylthiothiophene-2-carboxylatehydrobromide: Methyl4-(2-bromoacetyl)-5-methylthiothiophene-2-carboxylate (111 mg, 0.35mmol) was allowed to react with 4-methylphenylmethylthiourea asdescribed in Example 154, step (a) to give 125 mg (81% yield) of methyl4-(2-{[(4-methylphenyl)methyl]amino}(1,3-thiazol-4-yl))-5-methylthiothiophene-2-carboxylatehydrobromide. Mass Spectrum (ESI) m/z calcd. for C₁₈H₁₈N₂O₂S₂, 358.5(M+H), found 359.1.

b)4-(2-{[(4-Methylphenyl)methyl]amino}(1,3-thiazol-4-yl))-5-methylthiothiophene-2-carboxamidinehydrochloride: Methyl4-(2-{[(4-methylphenyl)methyl]amino}(1,3-thiazol-4-yl))-5-methylthiothiophene-2-carboxylatehydrobromide (118 mg, 0.26 mmol) was treated as described in Example154, step (b) to give 58.2 mg (54% yield) of4-(2-{[(4-methylphenyl)methyl]amino}(1,3-thiazol-4-yl))-5-methylthiothiophene-2-carboxamidinehydrochloride. ¹H NMR (DMSO-d₆, 300 MHz) δ 2.27 (s, 3H), 2.66 (s, 3H),4.49 (d, 2H, J=5.7 Hz), 6.88 (s, 1H), 7.13 (d, 2H, J=7.8 Hz), 7.27 (d,2H, J=8.0 Hz), 8.20 (t, 1H, J=5.8 Hz), 8.42 (s, 1H), 8.90 (bs, 2H), 9.27(bs, 2H); Mass Spectrum (ESI) m/z calcd. for C₁₇H₁₈N₄S₃, 374.55 (M+H),found 375.2.

EXAMPLE 177

a) Amino{[4-(4-chlorophenoxy)phenyl]amino}methane-1-thione: Unlessotherwise indicated, all thioureas, isothiocyanates, thioamides andamines were purchased from Maybridge Chemical Co. Ltd.(Cornwall, U.K.),Transworld Chemical Co. (Rockville, Md.), or Aldrich Chemical Co.,(Milwaukee, Wis.). (i) 4-Amino-4′-chlorodiphenylether (TCI America,Portland Oreg., 520 mg, 2.03 mmol) was slurried in 10 mL of ether andtreated with ca. 1 mL of ether saturated with HCl gas. After 5 min. thesolvent was removed in vacuo. To a stirring biphasic solution amine-HClsalt in 20 mL CHCl₃-sat'd NaHCO₃ (1:1, v/v) at ambient temperature wasadded thiophosgene (1.2 equiv, 2.4 mmol) in 5 mL of CHCl₃ dropwise viaan addition funnel. The reaction was vigorously stirred for 1 h (TLC,50% ethyl acetate-hexanes indicates clean conversion to a higher Rfspot), at which time the layers were separated, the aqueous layerextracted with CHCl₃ (1×20 mL), and the combined organic layers washedwith brine (1×20 mL) and dried (Na₂SO₄). Concentration of the solvent invacuo yielded the crude 4-(4-chlorophenoxy)-phenylisothiocyanate (414mg). (ii) The 4-(4-chlorophenoxy)-phenylisothiocyanate was transferredto an Ace Glass pressure tube equipped with a Teflon coated stir bar andtreated with a 2.0 M solution of NH₃ in 5 ml methanol (Aldrich ChemicalCo., Milwaukee, Wis.)). The tube was sealed and immersed in a 80° C. oilbath. After 2 h, the reaction was cooled to 0° C. in an ice bath. Theprecipitates were filtered and dried under vacuum to yieldamino{[4-(4-chlorophenoxy)phenyl]amino}methane-1-thione (328 mg, 79%).¹H NMR (DMSO-d₆, 300 MHz) δ 7.02 (m, 4H), 7.41 (m, 4H), 9.65 (s, 1H);Mass Spectrum (ESI) m/z calcd. for C₁₃H₁₁ClN₂OS, 278.8 (M+H), found279.4.

b) Methyl4-(2-{[4-(4-chlorophenoxy)phenyl]amino}(1,3-thiazol-4-yl))-5-methylthiothiophene-2-carboxylatehydrobromide: Methyl4-(2-bromoacetyl)-5-methylthiothiophene-2-carboxylate (309 mg, 1.0 mmol)was allowed to react withamino{[4-(4-chlorophenoxy)phenyl]amino}methane-1-thione (297 mg) asdescribed in Example 154, step (a) to give 410 mg (72% yield) of methyl4-(2-{[4-(4-chlorophenoxy)phenyl]amino}(1,3-thiazol-4-yl))-5-methylthiothiophene-2-carboxylatehydrobromide. Mass Spectrum (ESI) m/z calcd. for C₂₂H₁₇ClN₂O₃S₃, 489.1(M+H), found 489.1.

c)4-(2-{[4-(4-Chlorophenoxy)phenyl]amino}(1,3-thiazol-4-yl))-5-methylthiothiophene-2-carboxamidinehydrochloride: Methyl4-(2-{[4-(4-chlorophenoxy)phenyl]amino}(1,3-thiazol-4-yl))-5-methylthiothiophene-2-carboxylatehydrobromide (300 mg, 0.52 mmol) was treated as described in Example154, step (b) to give 129.9 mg (49% yield) of4-(2-{[4-(4-chlorophenoxy)phenyl]amino}(1,3-thiazol-4-yl))-5-methylthiothiophene-2-carboxamidinehydrochloride. ¹H NMR (DMSO-d₆, 300 MHz) δ 2.72 (s, 3H), 6.97 (m, 2H),7.07 (m, 2H), 7.15 (s, 1H), 7.40 (m, 2H), 7.85 (m, 2H), 8.46 (s, 1H),8.82 (bs, 2H), 9.27 (bs, 2H), 10.43 (bss, 1H); Mass Spectrum (ESI) m/zcalcd. for C₂₁H₁₇ClN₄OS₃, 473.1 (M+H), found 473.2, 475.1.

EXAMPLE 178

a) Methyl5-methylthio-4-[2-({4-[5-(trifluoromethyl)(2-pyridyloxy)]phenyl}amino)(1,3-thiazol-4-yl)]thiophene-2-carboxylate:Methyl 4-(2-bromoacetyl)-5-methylthiothiophene-2-carboxylate (70 mg,0.23 mmol) was allowed to react with4-[5-(trifluoromethyl)pyrid-2-yloxy]thiobenzamide (50 mg) as describedin Example 154, step (a) to give 115 mg (98% yield) of methyl5-methylthio-4-[2-({4-[5-(trifluoromethyl)(2-pyridyloxy)]phenyl}amino)(1,3-thiazol-4-yl)]thiophene-2-carboxylate.¹H NMR (DMSO-d₆, 300 MHz) δ 2.70 (s, 3H), 3.85 (s, 3H), 7.38 (m, 3H),8.10 (m, 1H), 8.18 (s, 1H), 8.28 (dd, 1H, J=2.7, 8.8 Hz), 8.32 (s, 1H),8.60 (m, 1H); Mass Spectrum (ESI) m/z calcd. for C₂₂H₁₅F₃N₂O₃S₃, 508.56(M+H), found 509.2.

b)5-Methylthio-4-[2({4-[5-(trifluoromethyl)(2-pyridyloxy)]phenyl}amino)(1,3-thiazol-4-yl)]thiophene-2-carboxamidinehydrochloride: Methyl5-methylthio-4-[2-({4-[5-(trifluoromethyl)(2-pyridyloxy)]phenyl}amino)(1,3-thiazol-4-yl)]thiophene-2-carboxylate(95 mg, 0.18 mmol) was treated as described in Example 154, step (b) togive 30.3 mg (32% yield) of5-methylthio-4-[2-({4-[5-(trifluoromethyl)(2-pyridyloxy)]phenyl}amino)(1,3-thiazol-4-yl)]thiophene-2-carboxamidinehydrochloride. ¹H NMR (DMSO-d₆, 300 MHz) δ 2.75 (s, 3H), 7.34 (d, 1H,J=8.7 Hz), 7.41 (m, 2H), 8.01 (s, 1H), 8.10-8.14 (m, 2H), 8.29 (dd, 1H,J=2.5, 8.4 Hz), 8.60 (m, 1H), 8.63 (s, 1H), 8.91 (bs, 2H), 9.31 (bs,2H); Mass Spectrum (ESI) m/z calcd. for C₂₁H₁₅F₃N₄OS₃, 492.6 (M+H),found 493.1.

EXAMPLE 179

a) Methyl4-(2-{[4-phenoxyphenyl]amino}(1,3-thiazol-4-yl))-5-methylthiothiophene-2-carboxylatehydrobromide: Methyl4-(2-bromoacetyl)-5-methylthiothiophene-2-carboxylate (200 mg, 0.64mmol) was allowed to react with 4-phenoxyphenylthiourea (158 mg) asdescribed in Example 154, step (a) to give 300 mg (88% yield) of methyl4-(2-{[4-(phenoxy)phenyl]amino}(1,3-thiazol-4-yl))-5-methylthiothiophene-2-carboxylatehydrobromide. Mass Spectrum (ESI) m/z calcd. for C₂₂H₁₈N₂O₃S₃, 454.6(M+H), found 455.2.

b)4-(2-{[4-Phenoxyphenyl]amino}(1,3-thiazol-4-yl))-5-methylthiothiophene-2-carboxamidinehydrochloride: Methyl4-(2-{[4-(phenoxy)phenyl]amino}(1,3-thiazol-4-yl))-5-methylthiothiophene-2-carboxylatehydrobromide (230 mg, 0.42 mmol) was treated as described in Example154, step (b) and purified by preparative thin layer chromatography (20%methanol-CH₂Cl₂-sat'd. NH₃, 500 mm silica gel plate, J. T. Baker,Phillipsburg, N.J.) to give 86 mg (47% yield) of the product. A 46 mgaliquot was dissolved in 1 mL of methanol, treated with 3 drops of ethersaturated with HCl gas, and concentrated in vacuo with toluene (2×5mL)to give 42.3 mg (21% yield) of4-(2-{[4-phenoxyphenyl]amino}(1,3-thiazol-4-yl))-5-methylthiothiophene-2-carboxamidinehydrochloride. ¹H NMR (DMSO-d₆, 300 MHz) δ 2.71 (s, 3H), 6.97-7.11 (m,4H), 7.15 (s, 1H), 7.36 (m, 2H), 7.72, 7.85 (d, 2H rotomer, J=8.7 Hz),8.36, 8.55 (s, 1H rotomer), 9.00 (bs, 2H), 9.35 (bs, 2H), 10.49 (s, 1H);Mass Spectrum (ESI) m/z calcd. for C₂₁H₁₈N₄OS₃, 438.6 (M+H), found 439.2

EXAMPLE 180

a) Amino{[4-(phenylamino)phenyl]amino}methane-1-thione:4-Aminodiphenylamine (500 mg, 2.71 mmol) was treated as described inExample 177, step (a) and recrystallized from toluene to give 350 mg(53% yield) of amino{[4-(phenylamino)phenyl]amino}methane-1-thione. ¹HNMR (DMSO-d₆, 300 MHz) δ 6.80 (m, 1H), 7.01-7.24 (m, 8H), 8.15 (s, 1H),9.45 (s, 1H); Mass Spectrum (ESI) m/z calcd. for C₁₃H₁₃N₃S, 243.33(M+H), found 244.2.

b) Methyl5-methylthio-4-(2-{[4-(phenylamino)phenyl]amino}(1,3-thiazol-4-yl))thiophene-2-carboxylatehydrobromide: Methyl4-(2-bromoacetyl)-5-methylthiothiophene-2-carboxylate (90 mg, 0.28 mmol)was allowed to react withamino{[4-(phenylamino)phenyl]amino}methane-1-thione (70.8 mg) asdescribed in Example 154, step (a) to give 71 mg (47% yield) of methyl5-methylthio-4-(2-{[4-(phenylamino)phenyl]amino}(1,3-thiazol-4-yl))thiophene-2-carboxylatehydrobromide. ¹H NMR (DMSO-d₆, 300 MHz) δ 2.66 (s, 3H), 3.82 (s, 3H),6.73 (m, 1H), 6.96-7.24 (m, 9H), 7.63 (d, 1H, J=8.6 Hz), 8.12 (s, 1H),10.13 (bs, 1H); Mass Spectrum (ESI) m/z calcd. for C₂₂H₁₉N₃O₂S₃, 453.60(M+H), found 454.2.

c) 5-Methylthio-4-(2-{[4-(phenylamino)phenyl]amino}(1,3-thiazol-4-yl))thiophene-2-carboxamidine hydrochloride:Methyl5-methylthio-4-(2-{[4-(phenylamino)phenyl]amino}(1,3-thiazol-4-yl))thiophene-2-carboxylatehydrobromide (71 mg, 0.13 mmol) was treated as described in Example 154,step (b) to give 23.3 mg (38% yield) of5-methylthio-4-(2-{[4-(phenylamino)phenyl]amino}(1,3-thiazol-4-yl))thiophene-2-carboxamidinehydrochloride. ¹H NMR (DMSO-d₆, 300 MHz) δ 2.72 (s, 3H), 6.74 (t, 1H,J=7.3 Hz), 6.98 (d, 1H, J=7.6 Hz), 7.08 (m, 2H), 7,18 (m, 2H), 7.66 (d,2H, J=8.9 Hz), 7.99 (s, 1H), 8.45 (s, 1H), 9.03 (bs, 4H), 10.17 (s, 1H);Mass Spectrum (ESI) m/z calcd. for C₂₁H₁₉N₅S₃, 437.59 (M+H), found438.2.

EXAMPLE 181

a) Amino{[4-benzylphenyl]amino}methane-1-thione: 4-Benzylphenylamine(500 mg, 2.73 mmol) was treated as described in Example 177, step (a) togive 410 mg (62% yield) of amino{[4-benzylphenyl]amino}methane-1-thione.¹H NMR (DMSO-d₆, 300 MHz) δ 3.89 (s, 2H), 7.14-7.28 (m, 9H), 9.59 (s,1H); Mass Spectrun (ESI) m/z calcd. for C₁₄H₁₄N₂S₃, 242.1 (M+H), found243.2

b) Methyl5-methylthio-4-(2-{[4-benzylphenyl]amino}(1,3-thiazol-4-yl))thiophene-2-carboxylatehydrobromide: Methyl4-(2-bromoacetyl)-5-methylthiothiophene-2-carboxylate (90 mg, 0.28 mmol)was allowed to react with amino{[4-benzylphenyl]amino}methane-1-thione(70.5 mg) as described in Example 154, step (a) to give 70.1 (47% yield)of methyl5-methylthio-4-(2-{[4-benzylphenyl]amino}(1,3-thiazol-4-yl))thiophene-2-carboxylatehydrobromide. ¹H NMR (DMSO-d₆, 300 MHz) δ 2.66 (s, 3H), 3.82 (s, 3H),3.87 (s 2H), 7.14-7.30 (m, 8H), 7.66 (d, 2H, J=8.5 Hz), 8.12 (s, 1H),10.23 (s, 1H); (Mass Spectrum (ESI) m/z calcd. for C₂₂H₁₉N₃O₂S₃, 453.6(M+H), found 454.2.

c)5-Methylthio-4-(2-{([4-benzylphenyl]amino}(1,3-thiazol-4-yl))thiophene-2-carboxamidinehydrochloride: Methyl5-methylthio-4-(2-{[4-benzylphenyl]amino}(1,3-thiazol-4-yl))thiophene-2-carboxylatehydrobromide (82.2 mg, 0.15 mmol) was treated as described in Example154, step (b) to give 33.4 mg (47% yield) of5-methylthio-4-(2-{[4-benzylphenyl]amino}(1,3-thiazol-4-yl))thiophene-2-carboxamidinehydrochloride. ¹H NMR (DMSO-d₆, 300 MHz) δ 2.72 (s, 3H), 3.89 (s, 2H),7.12 (s, 1H), 7.16-7.29 (m, 7H), 7.69 (d, 2H, J=8.6 Hz), 8.43 (s, 1H),9.02 (bs, 4H), 10.28 (s, 1H); Mass Spectrum (ESI) m/z calcd. forC₂₂H₂₀N₄S₃, 436.6 (M+H), found 437.2.

EXAMPLE 182

a) ({4-[(Aminothioxomethyl)amino]phenyl}sulfonyl)piperidine:4-Aminophenylsulphonylpiperidine (500 mg, 2.08 mol) was treated asdescribed in Example 177, step (a) to give 382 mg (61% yield)of({4-[(aminothioxomethyl)amino]phenyl}sulfonyl)piperidine. ¹H NMR(DMSO-d₆, 300 MHz) δ 1.34 (m, 2H), 1.53 (m, 4H), 2.85 (m, 4H), 7.62 (m,2H), 7.78 (m, 2H), 10.10 (bs, 1H); Mass Spectrum (ESI) m/z calcd. forC₁₂H₁₇N₃O₂S₂, 299.4 (M+H), found 300.2.

b) Methyl5-methylthio-4-(2-{[4-(piperidylsulfonyl)phenyl]amino}(1,3-thiazol-4-yl))thiophene-2-carboxylatehydrobromide: Methyl4-(2-bromoacetyl)-5-methylthiothiophene-2-carboxylate (90 mg, 0.28 mmol)was allowed to react with({4-[(aminothioxomethyl)amino]phenyl}sulfonyl)piperidine (87.1 mg) asdescribed in Example 154, step (a) to give 105 mg (63% yield) of methyl5-methylthio-4-(2-{[4-(piperidylsulfonyl)phenyl]amino}(1,3-thiazol-4-yl))thiophene-2-carboxylatehydrobromide. ¹H NMR (DMSO-d₆, 300 MHz) δ 1.33 (m, 2H), 1.52 (m, 4H),2.69 (s,3H), 2.84 (m, 4H), 3.82 (s, 3H), 7.43 (s, 1H), 7.66 (m, 2H),7.98 (m, 2H), 8.16 (s, 1H), 10.85 (s, 1H); (Mass Spectrum (ESI) m/zcalcd. for C₂₁H₂₃N₃O₄S₄, 509.69 (M+H), found 510.2.

c)5-Methylthio-4-(2-{[4-(piperidylsulfonyl)phenyl]amino}(1,3-thiazol-4-yl))thiophene-2-carboxamidinehydrochloride: Methyl5-methylthio-4-(2-{[4-(piperidylsulfonyl)phenyl]amino}(1,3-thiazol-4-yl))thiophene-2-carboxylatehydrobromide (105 mg, 0.17 mmol) was treated as described in Example154, step (b) to give 30.3 mg (34% yield) of5-methylthio-4-(2-{[4-(piperidylsulfonyl)phenyl]amino}(1,3-thiazol-4-yl))thiophene-2-carboxamidinehydrochloride. ¹H NMR (DMSO-d₆, 300 MHz) δ 1.36 (m, 2H), 1.54 (m, 4H),2.76 (s, 3H), 2.86 (m, 4H), 7.30 (s, 1H), 7.68 (d, 2H, J=8.8 Hz), 8.03(d, 2H, J=8.8 Hz), 8.51 (s, 1H), 8.84 (bs, 2H), 9.28 (bs, 2H), 10.94 (s,1H); Mass Spectrum (ESI) m/z calcd. for C₂₀H₂₃N₅O₂S₅, 493.69 (M+H),found 494.2.

EXAMPLE 183

a) Amino(3-quinolylamino)methane-1-thione: 3-Aminoquinoline (500 mg,3.46 mmol) was treated as described in Example 177, step (a) to give 285mg (41% yield) of amino(3-quinolylamino)methane-1-thione. ¹H NMR(DMSO-d₆, 300 MHz) δ 7.57 (m, 1H), 7.67 (m, 1H), 7.94 (m, 2H), 8.41 (d,1H, J=2.4 Hz), 8.85 (d, 1H, J=2.5 Hz), 10.03 (s, 1H); Mass Spectrum(ESI) m/z calcd. for C₁₀H₉N₃S, 203.3 (M+H), found 204.1.

b) Methyl5-methylthio-4-[2-(3-quinolylamino)(1,3-thiazol-4-yl)]thiophene-2-carboxylate:Methyl 4-(2-bromoacetyl)-5-methylthiothiophene-2-carboxylate (90 mg,0.28 mmol) was allowed to react withamino(3-quinolylamino)methane-1-thione (59.1 mg) as described in Example154, step (a) to give 107.5 mg (78% yield) of methyl5-methylthio-4-[2-(3-quinolylamino)(1,3-thiazol-4-yl)]thiophene-2-carboxylatehydrobromide. ¹H NMR (DMSO-d₆, 300 MHz) δ 2.75 (s, 3H), 3.84 (s, 3H),7.52 (s, 1H), 7.92-8.05 (m, 2H), 8.22 (s, 1H), 9.22 (m, 2H); MassSpectrun (ESI) m/z calcd. for C₁₉H₁₅N₃O₂S₃, 413.54 (M+H), found 414.1.

c)5-Methylthio-4-[2-(3-quinolylamino)(1,3-thiazol-4-yl)]thiophene-2-carboxamidinehydrochloride: Methyl5-methylthio-4-[2-(3-quinolylamino)(1,3-thiazol-4-yl)]thiophene-2-carboxylatehydrobromide (107.5 mg, 0.21 mmol) was treated as described in Example154, step (b) to give 4.5 mg (4.9% yield) of5-methylthio-4-[2-(3-quinolylamino)(1,3-thiazol-4-yl)]thiophene-2-carboxamidinehydrochloride. ¹H NMR (DMSO-d₆, 300 MHz) δ 2.80 (s, 3H), 7.29 (s, 1H),7.59 (m, 2H), 7.93 (m, 2H), 8.54 (s, 1H), 8.89 (bs, 2H), 8.91 (m, 1H),9.16 (m, 1H), 9.29 (bs, 2H), 10.97 (s, 1H); Mass Spectrum (ESI) m/zcalcd. for C₁₈H₁₅N₅S₃, 397.5 (M+H), found 398. 1.

EXAMPLE 184

a) Methyl5-methylthio-4-[2-(2-naphthylamino)(1,3-thiazol-4-yl)]thiophene-2-carboxylatehydrobromide: Methyl4-(2-bromoacetyl)-5-methylthiothiophene-2-carboxylate (65 mg, 0.21 mmol)was allowed react with 2-napthylthiourea (42.4 mg) as described inExample 154, step (a) to give 82.5 mg (80% yield)of methyl5-methylthio-4-[2-(2-naphthylamino)(1,3-thiazol-4-yl)]thiophene-2-carboxylatehydrobromide. ¹H NMR (DMSO-d₆, 300 MHz) δ 2.67 (s, 3H), 3.83 (s, 3H),7.31 (s, 1H), 7.50-7.67 (m, 4H), 7.93 (m, 1H), 8.15 (s, 1H), 8.31-8.35(m, 1H), 8.46 (d, 1H, J=7.6), 10.22 (s, 1H)); Mass Spectrum (ESI) m/zcalcd. for C₂₀H₁₆N₂O₂S₃, 412.6 (M+H), found 413.1.

c)5-Methylthio-4-[2-(2-naphthylamino)(1,3-thiazol-4-yl)]thiophene-2-carboxamidinehydrochloride: Methyl5-methylthio-4-[2-(2-naphthylamino)(1,3-thiazol-4-yl)]thiophene-2-carboxylatehydrobromide (42.7 mg, 0.086 mmol) was treated as described in Example154, step (b) to give 5.8 mg (16% yield) of5-methylthio-4-[2-(2-naphthylamino)(1,3-thiazol-4-yl)]thiophene-2-carboxamidinehydrochloride. ¹H NMR (DMSO-d₆, 300 MHz) δ 2.72 (s, 3H), 7.12-7.27 (m,3H), 7.50-7.68 (m, 3H), 7.94 (m, 1H), 8.32-8.35 (m, m, 1H), 8.51 (s,1H), 8.97 (bs, 2H), 9.34 (bs, 2H), 10.26 (s, 1H); Mass Spectrum (ESI)m/z calcd. for C₁₉H₁₆N₄S₃, 396.6 (M+H), found 397.2.

EXAMPLE 185

a) Methyl4-[2-(2H-benzo[3,4-d]1,3-dioxolan-5-ylamino)(1,3-thiazol-4-yl)]5-methylthiothiophene-2-carboxylatehydrobromide: Methyl4-(2-bromoacetyl)-5-methylthiothiophene-2-carboxylate (65 mg, 0.21 mmol)was allowed to react with 2,3-methylenedioxyphenylthiourea (41.2 mg) asdescribed in Example 154, step (a) to give 51 mg (50% yield) of methyl4-[2-(2H-benzo[3,4-d]1,3-dioxolan-5-ylamino)(1,3-thiazol-4-yl)]-5-methylthiothiophene-2-carboxylatehydrobromide. ¹H NMR (DMSO-d₆, 300 MHz) δ 2.66 (s, 3H), 3.83 (s, 3H),5.98 (s, 2H), 6.84-6.89 (m, 1H), 6.96, 7.04 (dd, 1H rotomer, J=2.2, 8.5Hz), 7.25 (s, 1H), 7.46, 7.60 (d, 1H rotomer, J=2.1 Hz), 8.05, 8.13 (s,1H rotomer), 10.19, 10.34 (s, 1H, rotomer); Mass Spectrum (ESI) m/zcalcd. for C₁₇H₁₄N₂O₄S₃, 406.5 (M+H), found 407.1.

b)4-[2-(2H-Benzo[3,4-d]1,3-dioxolan-5-ylamino)(1,3-thiazol-4-yl)]-5-methylthiothiophene-2-carboxamidinehydrochloride: Methyl4-[2-(2H-benzo[3,4-d]1,3-dioxolan-5-ylamino)(1,3-thiazol-4-yl)]-5-methylthiothiophene-2-carboxylatehydrobromide (51 mg, 0.10 mmol) was treated as described in Example 154,step (b) to give 16.6 mg (39% yield) of4-[2-(2H-benzo[3,4-d]1,3-dioxolan-5-ylamino)(1,3-thiazol-4-yl)]-5-methylthiothiophene-2-carboxamidinehydrochloride. ¹H NMR (DMSO-d₆, 300 MHz) δ 2.71(s, 3H), 5.98 (s, 2H),6.87 (d, 1H, J=8.2 Hz), 7.09-7.13 (m, 2H), 7.67 (d, 1H, J=2.4 Hz), 8.50(s, 1H), 8.95 (bs, 2H), 9.33 (bs, 2H), 10.30 (s, 1H); Mass Spectrum(ESI) m/z calcd. for C₁₆H₁₄N₄O₂S3, 390.51 (M+H), found 391.2;

EXAMPLE 186

a) Amino[(7-bromofluoren-2-yl)amino]methane-1-thione:2-Amino-7-bromofluorene (500 mg, 1.90 mmol) was treated as described inExample 177, step (a) to give 128 mg (21% yield) ofamino[(7-bromofluoren-2-yl)amino]methane-1-thione. ¹H NMR (DMSO-d₆, 300MHz) δ 3.35 (s, 2H), 7.35 (d, 1H, J=8.3 Hz), 7.54 (d, 1H, J=8.0 Hz),7.66 (s, 1H), 7.77-7.87 (m, 3H), 9.80 (s, 1H); Mass Spectrum (ESI) m/zcalcd. for C₁₄H₁₁BrN₂S, 319.2 (M+H), found 320.1, 321.1.

b) Methyl4-{2-[(7-bromofluoren-2-yl)amino](1,3-thiazol-4-yl)}-5-methylthiothiophene-2-carboxylatehydrobromide: Methyl4-(2-bromoacetyl)-5-methylthiothiophene-2-carboxylate (90 mg, 0.28 mmol)was allowed to react withamino[(7-bromofluoren-2-yl)amino]methane-1-thione (92.8 mg) as describedin Example 154, step (a) to give 141 mg (82% yield) of methyl4-{2-[(7-bromofluoren-2yl)amino](1,3-thiazol-4-yl)}-5-methylthiothiophene-2-carboxylatehydrobromide. ¹H NMR (DMSO-d₆, 300 MHz) δ 2.70 (s, 3H), 3.83 (s, 3H),3.93 (s, 2H), 7.33 (s, 1H), 7.51 (dd, 1H, J=1.9, 8.0 Hz), 7.65 (dd, 1H,J=2.0, 8.4 Hz), 7.74 (ad, 2H, J=8.3 Hz), 7.83 (ad, 1H, J=8.4 Hz), 8.18(s, 1H), 8.23 (d, 1H, J=1.4 Hz), 10.47 (s, 1H).

c)4-{2-[(7-Bromofluoren-2-yl)amino](1,3-thiazol-4-yl)}-5-methylthiothiophene-2-carboxamidinehydrochloride: Methyl4-{2-[(7-bromofluoren-2-yl)amino](1,3-thiazol-4-yl)}-5-methylthiothiophene-2-carboxylatehydrobromide (100 mg, 0.15 mmol) was treated as described in Example154, step (b) to give 3.3 mg (4% yield) of4-{2-[(7-bromofluoren-2-yl)amino](1,3-thiazol-4-yl)}-5-methylthiothiophene-2-carboxamidinehydrochloride. ¹H NMR (DMSO-d₆, 300 MHz) δ 2.76 (s, 3H), 3.95 (s, 2H),7.18 (s, 1H), 7.54 (dd, 1H, J=1.8, 10.0 Hz), 7.67-7.76 (m, 3H), 7.85 (d,1H, J=8.2 Hz), 8.23 (s, 1H), 8.50 (s, 1H), 10.53 (s, 1H); Mass Spectrum(ESI) m/z calcd. for C₂₂H₁₇BrN₄S₃, 513.5 (M+H), found 513.1, 515.1.

EXAMPLE 187

a) Methyl4-{2-[(4-cyclohexylphenyl)amino](1,3-thiazol-4-yl)}-5-methylthiothiophene-2-carboxylatehydrobromide: Methyl4-(2-bromoacetyl)-5-methylthiothiophene-2-carboxylate (65 mg, 0.21 mmol)was allowed to react with 4-cyclohexylphenylthiourea (49.2 mg) asdescribed in Example 154, step (a) to give 45 mg (41% yield) of methyl4-{2-[(4-cyclohexylphenyl)amino](1,3-thiazol-4-yl)}-5-methylthiothiophene-2-carboxylatehydrobromide. ¹H NMR (DMSO-d₆, 300 MHz) δ 1.23-1.39 (m, 5H), 1.71-1.79(m, 5H), 2.68 (s, 3H), 3.83 (s, 3H), 7.16 (d, 2H, J=8.6 Hz), 7.26 (s,1H), 7.65 (d, 2H, J=8.7 Hz), 8.14 (s, 1H), 10.19 (s, 1H); Mass Spectrum(ESI) m/z calcd. for C₂₂H₂₄N₂O₂S₃, 444.64 (M+H), found 445.2.

b)4-{2-(4-Cyclohexylphenyl)amino(1,3-thiazol-4-yl)}-5-methylthiothiophene-2-carboxamidinehydrochloride: Methyl4-{2-[(4-cyclohexylphenyl)amino](1,3-thiazol-4-yl)}-5-methylthiothiophene-2-carboxylatehydrobromide (31.1 mg, 0.059 mmol) was treated as described in Example154, step (b) to give 12.8 mg (47% yield) of4-{2-[(4-cyclohexylphenyl)amino](1,3-thiazol-4-yl)}-5-methylthiothiophene-2-carboxamidinehydrochloride. ¹H NMR (DMSO-d₆, 300 MHz) δ 1.33-1.40 (m, 5H), 1.68-1.79(m, 5H), 2.44 (m, 1H), 2.73 (s, 3H), 7.12 (s, 1H), 7.18 (d, 2H, J=8.7Hz), 7.68 (d, 2H, J=8.7 Hz), 8.47 (s, 1H), 8.85 (bs, 2H), 9.32 (bs, 2H),10.28 (s, 1H); Mass Spectrum (ESI) m/z calcd. for C₂₁H₂₄N₄S₃, 428.64(M+H), found 429.2.

EXAMPLE 188

a) Amino{[4-(phenyldiazenyl)phenyl]amino}methane-1-thione:4-Phenylazophenylisothiocyanate (314 mg, 1.30 mmol) was treated asdescribed in Example 177, step (a), part (ii), to give 295 mg (88%yield) of amino{[4-(phenyldiazenyl)phenyl]amino}methane-1-thione. ¹HNMR(DMSO-d₆, 300MHz) δ 6.84 (m, 1H), 7.57 (m, 2H), 7.73 (m, 2H),7.85-7.89 (m, 4H), 10.04 (s, 1H); Mass Spectrum (ESI) m/z calcd. forC₁₃H₁₂N₄S, 256.3 (M+H), found 257.2.

b) Methyl5-methylthio-4-(2-{[4-(phenyldiazenyl)phenyl]amino}(1,3-thiazol-4-yl))thiophene-2-carboxylatehydrobromide: Methyl4-(2-bromoacetyl)-5-methylthiothiophene-2-carboxylate (65 mg, 0.21 mmol)was allowed to react with amino{[4-(phenyldiazenyl)phenyl]amino}methane-1-thione (53.8 mg) as describedin Example 154, step (a) to give 80.6 mg (70% yield) of methyl5-methylthio-4-(2-{[4-(phenyldiazenyl)phenyl]amino}(1,3-thiazol-4-yl))thiophene-2-carboxylatehydrobromide. ¹H NMR (DMSO-d₆, 300 MHz) δ 2.72 (s, 3H), 3.84 (s, 3H),7.46 (s, 1H), 7.49-7.61 (m, 3H), 7.84 (m, 2H), 7.91-8.02 (m, 4H), 8.20(s, 1H), 10.83 (s, 1H); Mass Spectrum (ESI) m/z calcd. for C₂₂H₁₈N₄O₂S₃,466.6 (M+H), found 467.1.

c)5-Methylthio-4-(2-{[4-(phenyldiazenyl)phenyl]amino}to)(1,3-thiazol-4-yl))thiophene-2-carboxamidinehydrochloride: Methyl5-methylthio-4-(2-{[4-(phenyldiazenyl)phenyl]amino}(1,3-thiazol-4-yl))thiophene-2-carboxylatehydrobromide (47.7 mg, 0.087 mmol) was treated as described in Example154, step (b) to give 32.8 mg (77% yield) of5-methylthio-4-(2-{[4-(phenyldiazenyl)phenyl]amino}(1,3-thiazol-4-yl))thiophene-2-carboxamidinehydrochloride. ¹H NMR (DMSO-d₆, 300 MHz) δ 2.78 (s, 3H), 7.26 (s, 1H),7.49-7.63 (m, 3H), 7.66-7.74 (m, 3H), 7.84-8.08 (m, 3H), 8.60 (s, 1H),11.02 (bs, 1H); Mass Spectrum (ESI) m/z calcd. for C₂₁H₁₈N₆S₃, 450.6(M+H), found 451.1.

EXAMPLE 189

a) {3-[(Aminothioxomethyl)amino]phenyl}methan-1-ol: 3-Aminobenzylalcohol (550 mg, 4.46 mmol) was treated as described in Example 177,step (a) to give 618 mg (76% yield) of{3-[(aminothioxomethyl)amino]phenyl}methan-1-ol. ¹H NMR (DMSO-d₆, 300MHz) δ 4.47 (d, 2H, J=5.6 Hz), 5.19 (t, 1H, J=5.7 Hz), 7.06 (d, 1H,J=6.2 Hz), 7.18-7.30 (m, 3H), 9.73 (s, 1H).

b)Methyl-5-methylthio4-(2-{[3-(hydroxymethyl)phenyl]amino}(1,3-thiazol-4-yl))-thiophene-2-carboxylatehydrobromide: Methyl4-(2-bromoacetyl)-5-methylthiothiophene-2-carboxylate (1.01 g, 3.26mmol) was allowed to react with of{3-[(aminothioxomethyl)amino]phenyl}methan-1-ol as described in Example154, step (a) to give 1.42 g (92% yield) ofmethyl-5-methylthio-4-(2-{[3-(hydroxymethyl)phenyl]amino}(1,3-thiazol-4-yl))-thiophene-2-carboxylatehydrobromide. ¹H NMR (DMSO-d₆, 300 MHz) δ 2.67 (s, 3H), 3.83 (s, 3H),4.49 (s, 2H), 6.92 (m, 1H), 7.23-7.31 (m, 2H), 7.60 (m, 1H), 7.81 (bs,1H), 8.17 (s, 1H), 10.29 (bs, 1H).

c) 5-Methylthio4-(2-{[3-(hydroxymethyl)phenyl]amino}1,3-thiazol-4-yl))-thiophene-2-carboxamidinehydrochloride:Methyl-5-methylthio4-(2-{[3-(hydroxymethyl)phenyl]amino}(1,3-thiazol-4-yl))-thiophene-2-carboxylatehydrobromide (700 mg, 1.47 mmol) was treated as described in Example154, step (b) using 1:9:1 methanol-CH₂Cl₂-DMF as eluent to give 195 mg(32% yield) of 5-methylthio4-(2-{[3-(hydroxymethyl)phenyl]amino}(1,3-thiazol-4-yl))-thiophene-2-carboxamidinehydrochloride. ¹H NMR (DMSO-d₆, 300 MHz) δ 2.71 (s, 3H), 4.50 (s, 2H),6.93 (d, 1H, J=7.6 Hz), 7.15 (s, 1H), 7.21-7.27 (m, 1H), 7.38 (bs, 1H),7.65 (d, 1H, J=8.1 Hz), 7.80 (s, 1H), 8.53 (s, 1H), 8.94 (bs, 2H), 9.32(bs, 2H), 10.37 (s,1H); Mass Spectrum (ESI) m/z calcd. for C₁₆H₁₆N₄OS₃,376.5 (M+H), found 377.2.

EXAMPLE 190

a)(tert-Butoxy)-N-[(4-{2-[(3-hydroxymethylphenyl)amino](3-thiazol-4-yl)}-5-methylthio(2-thienyl))iminomethyl]-carboxamide:5-Methylthio4-(2-{[3-(hydroxymethyl)phenyl]amino}(1,3-thiazol-4-yl))-thiophene-2-carboxamidine(103 mg, 0.27 mmol) was slurried in THF (4 mL) and treated with 0.5 mLof 0.5 N NaOH. tert-Butyldicarbonate (0.40 mmol) was added in oneportion and the resulting mixture was stirred overnight. The reactionwas partitioned in CH₂Cl₂ and water. The organic layer was separated andwashed with brine (1×20 mL) and dried (Na₂SO₄). Removal of the solventin vacuo, followed by purification on preparative thin layerchromatography (500 mm silica gel plate, J. T. Baker, Phillipsburg,N.J., 1% methanol-CH₂Cl₂), gave 45 mg (35% yield) of((tert-Butoxy)-N-[(4-{2-[(3-hydroxymethylphenyl)amino](1,3-thiazol-4-yl)}-5-methylthio(2-thienyl))iminomethyl]-carboxamide.¹H NMR (DMSO-d₆, 300 MHz) δ 1.44 (s, 9H), 2.66 (s, 3H), 4.49 (d, 2H,J=5.7 Hz), 5.15 (t, 1 H, J=5.5 Hz), 6.92 (d, 1H, J=7.5 Hz), 6.96 (s,1H), 7.26 (m, 1H), 7.66 -7.75 (m, 2H), 8.38 (s, 1H), 8.98 (bs, 2H),10.24 (s, 1H).

b)(tert-Butoxy)-N-(imino{4-[2-({3-[(3-methylpiperidyl)methyl]phenyl}amino)(1,3-thiazol-4-yl)]-5-methylthio(2-thienyl){methyl)carboxamide:To a stirring solution of((tert-butoxy)-N-[(4-{2-[(3-hydroxymethylphenyl)amino](1,3-thiazol-4-yl)}-5-methylthio(2-thienyl))iminomethyl]-carboxamide(45 mg, 0.094 mmol) under N₂ was added triethylamine (2 equiv, 26.3 μl),followed by methansulfonyl chloride (Aldrich Chemical Co., Milwaukee,Wis., 0.13 mmol, 10.2 μl ). The reaction was stirred for 1 h, at whichtime the reaction was partitioned in CH₂Cl₂-water. The organic layer waswashed with brine (20 mL), filtered through a 5-cm pad of silica gel ina 15-mL fritted glass funnel and dried (Na₂SO₄). Removal of the solventin vacuo afforded the crude mesylate (44 mg) which was used immediatelywithout further purification. To 25.3 mg (0.045 mmol) of the mesylate in0.5 mL of DMF was added 3-methyl piperidine (0.18 mmol, 21.4 μL) and theresult was heated to 65° C. in an oil bath for 4 h. The reaction wasconcentrated in vacuo and purified by preparative thin layerchromatography (250 mm silica gel plate, 10% methanol-CH₂Cl₂, J. T.Baker, Phillipsburg, N.J.) to give 8.2 mg (32% yield) of(tert-butoxy)-N-(imino{4-[2-({3-[(3-methylpiperidyl)methyl]phenyl}amino)(1,3-thiazol-4-yl)]-5-methylthio(2-thienyl)}methyl)carboxamide.Mass Spectrum (ESI) m/z calcd. for C₂₇H₃₅N₅O₂S₃, 557.8 (M+H), found557.9, 458.2 (—C(O)OC(CH₃)₃.

c)4-[2-({3-[(3-Methylpiperidyl)methyl]phenyl}amino)(1,3-thiazol-4-yl)]-5-methylthiothiophene-2-carboxamidinehydrochloride: (tert-Butoxy)-N-(imino{4-[2-({3-[(3-methylpiperidyl)methyl]phenyl}amino)(1,3-thiazol-4-yl)]-5-methylthio(2-thienyl)}methyl)carboxamide(8.2 mg, 0.014 mmol) was stirred 2 mL of a 10% 3N HCl-ethyl acetatesolution at 0° C. for 30 min., at which time the solvent was removed invacuo to give 8 mg (100% yield) of the4-[2-({3-[(3-methylpiperidyl)methyl]phenyl}amino)(1,3-thiazol-4-yl)]-5-methylthiothiophene-2-carboxamidinehydrochloride. ¹H NMR (DMSO-d₆, 300 MHz) δ 0.83 (d, 3H, J=5.6 Hz),1.54-2.48 (m, 5H), 2.52-2.63 (m, 4H), 2.66 (s, 3H), 4.23 (d, 2H, J=4.8Hz), 7.15-7.23 (m, 2H), 7.41 (t, 1H, J=7.8 Hz), 7.86-7.92 (m, 2H), 8.63(s, 1H), 9.01 (bs, 2H), 9.42 (bs, 2H), 10.63 (s, 1H); (Mass Spectrum(ESI) m/z calcd. for C₂₂H₂₇N₅S₃, 457.7 (M+H), found 458.2.

EXAMPLE 191

a)Methyl-5-methylthio-4-{2-[(3-hydroxyphenyl)amino](1,3-thiazol-4-yl)}-thiophene-2-carboxylatehydrobromide: Methyl4-(2-bromoacetyl)-5-methylthiothiophene-2-carboxylate (60 mg, 0.19 mmol)was allowed to react with 3-15 hydroxyphenylthiourea (32.6 mg) asdescribed in Example 154, step (a) to give 80.2 mg (92% yield) ofmethyl-5-methylthio-4-{2-[(3-hydroxyphenyl)amino](1,3-thiazol-4-yl)}-thiophene-2-carboxylatehydrobromide. ¹H NMR (DMSO-d₆, 300 MHz) δ 2.67 (s, 3H), 3.83 (s, 3H),6.38 (d, 1H, J=7.6 Hz), 7.06-7.12 (m, 2H), 7.20-7.29 (m, 2H), 8.14(s,1H), 10.17(s, 1H).

b)4-{2-[(3-Hydroxyphenyl)amino](1,3-thiazol-4-yl)}-5-methylthiothiophene-2-carboxamidinehydrochloride:Methyl-5-methylthio-4-{2-[(3-hydroxyphenyl)amino](1,3-thiazol-4-yl)}-thiophene-2-carboxylatehydrobromide (460 mg, 1.0 mmol) was treated as described in Example 154,step (b) to give 215 mg (54% yield) of4-{2-[(3-hydroxyphenyl)amino](1,3-thiazol-4-yl)}-5-methylthiothiophene-2-carboxamidinehydrochloride. (Mass Spectrum (ESI) m/z calcd. for C₁₅H₁₄N₄OS₃, 362.5(M+H), found 363.2.

c)(tert-Butoxy)-N-[(4-{2-[(4-hydroxyphenyl)amino](1,3-thiazol-4-yl)}-5-methylthio(2-thienyl))iminomethyl]carboxamide:To a stirring solution of4-{2-[(3-hydroxyphenyl)amino](1,3-thiazol-4-yl)}-5-methylthiothiophene-2-carboxamidinehydrochloride (215 mg, 0.48 mmol) in 4 mL of CH₂Cl₂-DMF (3:1, v/v) wasadded di-isopropylethylamine (1.2 equiv). Di-tert-butyl dicarbonate (1.2equiv, 127 mg, Aldrich Chemicals, Milwaukee, Wis.) was then addeddropwise in 1 mL CH₂Cl₂ via an addition funnel. The reaction was allowedto stir overnight, partitioned in CH₂Cl₂—H₂O, and the layers separated.The organic layer was dried (Na₂SO₄) and concentrated in vacuo. Theresidue was purified by flash chromatography (1% methanol-CH₂Cl₂)to give60 mg (27% yield) of(tert-butoxy)-N-[(4-{2-[(4-hydroxyphenyl)amino](1,3-thiazol-4-yl)}-5-methylthio(2-thienyl))iminomethyl]carboxamide.¹H NMR (DMSO-d₆, 300 MHz) δ 1.44 (s, 9H), 2.72 (s, 3H), 6.38 (m, 1H),6.96 (s, 1H), 7.06-7.12 (m, 2H), 7.28 (m, 1H), 8.35 (s, 1H), 9.00 (bs,2H), 9.28 (s, 1H), 10.11 (s, 1H); Mass Spectrum (ESI) m/z calcd. forC₂₀H₂₂N₄O₃S₃, 462.6 (M+H), found 462.7, 363.2 [—C(O)OC(CH₃)₃].

d)(tert-Butoxy)-N-{[4-(2-{[3-(carbamoylmethoxy)phenyl]amino}(1,3-thiazol-4-yl))-5-methylthio(2-thienyl)]iminomethyl}carboxamide:To stirring solution of(tert-butoxy)-N-[(4-{2-[(4-hydroxyphenyl)amino](1,3-thiazol-4-yl)}-5-methylthio(2-thienyl))iminomethyl]carboxamide(65 mg, 0.14 mmol) in 1.5 mL of DMF was added sequentially Cs₂CO₃ (1.5equiv, 60.1 mg, Aldrich Chemicals, Milwaukee, Wis.), bromoacetamide (1.2equiv, 20.4 mg, Aldrich Chemicals, Milwaukee, Wis.), and a catalyticamount of KI. The reaction was warmed to 58° C. in an oil bath, stirredfor 48 h, at which time another 0.6 equiv of bromoacetamide was added.Stirring was continued for another 24 h, at which time the reaction wasfiltered and concentrated in vacuo. The residue was purified bypreparative thin layer chromatography (50% ethyl acetate-hexanes) togive 9 mg (12% yield) of(tert-butoxy)-N-{[4-(2-{[3-(carbamoylmethoxy)phenyl]amino}(1,3-thiazol-4-yl))-5-methylthio(2-thienyl)]iminomethyl}carboxamide.Mass Spectrum (ESI) m/z calcd. for C₂₂H₂₅N₅O₄S₃, 519.7 (M+H), found519.7, 420.7 [—C(O)OC(CH₃)₃].

e)4-(2-{[4-(Carbamoylmethoxy)phenyl]amino}(1,3-thiazol-4-yl))-5-methylthiothiophene-2-carboxamidinetrifluoroacetate: To a stirring suspensionof(tert-butoxy)-N-{[4-(2-{[3-(carbamoylmethoxy)phenyl]amino}(1,3-thiazol-4-yl))-5-methylthio(2-thienyl)]iminomethyl}carboxamide(ca. 4 mg, 0.007 mmol) in CH₂Cl₂-DMF (4 mL, 3:1 v/v) at 0° C. was added1 mL of trifluoroacetic acid. The homogeneous solution was stirred anadditional 40 min. at this temperature, warmed to ambient temperatureover a 30 min. period and concentrated in vacuo to give 4 mg (100%yield) of4-(2-{[4-(carbamoylmethoxy)phenyl]amino}(1,3-thiazol-4-yl))-5-methylthiothiophene-2-carboxamidinetrifluoroacetate. ¹H NMR (DMSO-d₆, 300 MHz) δ 2.75 (s, 3H), 4.21(d, 2H,J=5.7 Hz), 6.64 (dd, 1H, J=2.4,8.2 Hz), 6.97 (dd, 1H, J=1.1, 8.2 Hz),7.16 (s, 1H), 7.22 (m, 1H), 7.60-7.63 (m, 1H), 7.69-7.72 (m, 1H), 7.88(t, 1H, J=2.1 Hz), 8.42 (s, 1H); Mass Spectrum (ESI) m/z calcd. forC₁₇H₁₇N₅O₂S₃, 419.6 (M+H), found 420.1.

EXAMPLE 192

a) Isopropyl5-methyl-4-{2-[(3,4,5-trimethoxyphenyl)amino](1,3-thiazol-4-yl)}thiophene-2-carboxylatehydrobromide:Isopropyl-4-(2-bromoacetyl)-5-methylthiophene-2-carboxylate (84 mg, 0.27mmol) was allowed to react with 3,4,5-trimethoxyphenylthiourea (66.5 mg)as described in Example 154, step (a) to give 68 mg (48% yield) ofisopropyl5-methyl-4-{2-[(3,4,5-trimethoxyphenyl)amino](1,3-thiazol-4-yl)}thiophene-2-carboxylatehydrobromide. Mass Spectrum (ESI) m/z calcd. For C₂₁H₂₄N₂O₅S₂, 448.56(M+H), found 449.0.

b)5-Methyl-4-{2-[(3,4,5-trimethoxyphenyl)amino](1,3-thiazol-4-yl)}thiophene-2-carboxamidinehydrochloride: Isopropyl5-methyl-4-{2-[(3,4,5-trimethoxyphenyl)amino](1,3-thiazol-4-yl)}thiophene-2-carboxylatehydrobromide (59 mg, 0.11 mmol) was treated as described in Example 154,step (b) to give 24.4 mg (50% yield) of5-methyl-4-{2-[(3,4,5-trimethoxyphenyl)amino](1,3-thiazol-4-yl)}thiophene-2-carboxamidinehydrochloride. ¹H NMR (DMSO-d₆, 300 MHz) δ 2.81 (s, 3H), 3.61 (s, 3H),3.77 (s, 6H), 7.04 (s, 2H), 7.09 (s, 1H), 8.40 (s, 1H); Mass Spectrum(ESI) m/z calcd. for C₁₈H₂₀N₄O₃S₂, 404.5 (M+H), found 405.2.

EXAMPLE 193

a) Isopropyl5-methyl-4-{2-[4-phenoxyphenyl)amino](1,3-thiazol-4-yl)}thiophene-2-carboxylatehydrobromide:Isopropyl-4-(2-bromoacetyl)-5-methylthiophene-2-carboxylate (91 mg, 0.29mmol) was allowed to react with 4-phenoxyphenylthiourea (72.6 mg) asdescribed in Example 154, step (a) to give 115 mg (75% yield) ofisopropyl5-methyl-4-{2-[(4-phenoxyphenyl)amino](1,3-thiazol-4-yl)}thiophene-2-carboxylatehydrobromide. ¹H NMR (DMSO-d₆, 300 MHz) δ 1.28 (d, 6H, J=6.2 Hz), 2.70(s, 3H), 6.06 (quintet, 1H, J=6.2 Hz), 6.92-7.09 (m, 5H), 7.15 (s, 1H),7.30-7.37 (m, 2H), 7.56-7.70 (m, 2H), 7.98 (s, 1H); Mass Spectrum (ESI)m/z calcd. for C₂₄H₂₂N₂O₃S₂, 450.6 (M+H), found 451.2, 409.2[—CH(CH₃)₂].

b)5-Methyl-4-{2-[(4-phenoxyphenyl)amino](1,3-thiazol-4-yl)}thiophene-2-carboxamidinehydrochloride: Isopropyl5-methyl-4-{2-[(4-phenoxyphenyl)amino](1,3-thiazol-4-yl)}thiophene-2-carboxylatehydrobromide (95.5 mg, 0.17 mmol) was treated as described in Example154, step (b) to give 23.8 mg (32% yield) of5-methyl-4-{2-[(4-phenoxyphenyl)amino](1,3-thiazol-4-yl)}thiophene-2-carboxamidinehydrochloride. ¹H NMR (DMSO-d₆, 300 MHz) δ 82.76 (s, 3H), 6.95-7.12 (m,6H), 7.34-7.39 (m, 2H), 7.72-7.78 (m, 2H), 8.33 (s, 1H), 8.98 (bs, 3H),10.29 (bs, 1H); Mass Spectrum (ESI) m/z calcd. for C₂₁H₁₈N₄O₂S₃, 406.5(M+H), found 407.2.

EXAMPLE 194

a) Isopropyl5-methyl-4-[2-(phenylamino)(1,3-thiazol-4-yl)]-thiophene-2-carboxylatehydrobromide: Isopropyl4-(2-bromoacetyl)-5-methylthiophene-2-carboxylate (64 mg, 0.21 mmol) wasallowed to react with phenylthiourea (32.1 mg) as described in Example154, step (a) to give 80 mg (87% yield) of isopropyl5-methyl-4-[2-(phenylamino)(1,3-thiazol-4-yl)]-thiophene-2-carboxylatehydrobromide. Mass Spectrum (ESI) m/z calcd. for C₁₈H₁₈N₂O₂S₂, 358.5(M+H), found 359.2.

b)5-Methyl-4-[2-(phenylamino)(1,3-thiazol-4-yl)]thiophene-2-carboxamidinehydrochloride: Isopropyl5-methyl-4-[2-(phenylamino)(1,3-thiazol-4-yl)]-thiophene-2-carboxylatehydrobromide (74 mg, 0.16 mmol) was treated with phenylthiourea (24.3mg) as described in Example 154, step (b) to give 15 mg (28% yield) (of5-methyl-4-[2-(phenylamino)(1,3-thiazol-4-yl)]thiophene-2-carboxamidinehydrochloride, which was further purified by recrystallization frommethanol-water. ¹H NMR (DMSO-d₆, 300 MHz) δ 2.79 (s, 3H), 6.96 (t, 1H,J=7.2 Hz), 7.09 (s, 1H), 7.33 (t, 2H, J=7.5 Hz), 7.71 (d, 2H, J=7.7 Hz),8.39 (s, 1H), 8.95 (bs, 2H), 9.33 (bs, 2H), 10.37 (s, 1H); Mass Spectrum(ESI) m/z calcd. for C₁₅H₁₄N₄S₃, 314.4 (M+H), found 315.2.

EXAMPLE 195

a) Methyl4-(4-isoxazol-5-yl(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxylate:Methyl 4-(aminothioxomethyl)-5-methylthiothiophene-2-carboxylate (872mg, 2.51 mmol) was allowed to react with2-bromo-1-isoxazol-5-ylethan-1-one (737 mg, prepared from fromisoxazole-5-carbonyl chloride [Maybridge Chemicals, Cornwall, UK] asdescribed in Example 177, step (a) as described in Example 154, step (a)to give 704 mg (83% yield) of methyl4-(4-isoxazol-5-yl(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxylate.¹H NMR (DMSO-d₆, 300 MHz) δ 2.75 (s, 3H), 3.85 (s, 3H), 6.93 (d, 1H,J=1.8 Hz), 8.22 (s, 1H), 8.38 (s, 1H), 8.70 (d, 1H, J=1.85 Hz).

b)4-(4-Isoxazol-5-yl(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxamidinehydrochloride: Methyl4-(4-isoxazol-5-yl(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxylate(350 mg, 1.03 mmol) was treated as described in Example 154, step (b) togive 290 mg (78% yield) of4-(4-isoxazol-5-yl(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxamidinehydrochloride, of which an aliquot was further purified byrecrystallization from methanol-isopropanol-water (3:1:0.2, v/v/v). ¹HNMR (DMSO-d₆, 300 MHz) δ 2.79 (s, 3H), 6.93 (d, 1H, J=1.9 Hz), 8.45 (s,1H), 8.74 (m, 2H), 9.23 (bs, 2H), 9.53 (bs, 2H); Mass Spectrum(MALDI-TOF, CHCA matrix) m/z calcd. for C₁₂H₁₀N₄OS₃, 322.4 (M+H), found323.3.

EXAMPLE 196

a) Methyl4-[4-(2-hydroxyphenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxylate:Methyl 4-(aminothioxomethyl)-5-methylthiothiophene-2-carboxylate (808mg, 3.26 mmol) was allowed to react with 2-(2-bromoacetyl)hydroxybenzene(925 mg, prepared from 2-(chlorocarbonyl)phenyl acetate [AldrichChemicals, 20 Milwaukee, Wis.] as described in Example 177, step (a)) asdescribed in Example 154, step (a) to give 433 mg (37% yield) of methyl4-[4-(2-hydroxyphenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxylate.¹H NMR(DMSO-d₆, 300 MHz) δ 2.77 (s, 3H), 3.86 (s, 3H), 6.91-7.00 (m,2H), 7.23 (m, 1H), 8.14-8.19 (m, 2H), 8.24 (s, 1H); Mass Spectrum (ESI)m/z calcd. for C₁₆H₁₃NO₃S₃, 363.48 (M+H), found 364.2.

b)4-[4-(2-Hydroxyphenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxamidinehydrochloride: Methyl4-[4-(2-hydroxyphenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxylate(400 mg, 1.1 mmol) was treated as described in Example 154, step (b) togive 173 mg (41% yield) of4-[4-(2-hydroxyphenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxamidinehydrochloride. ¹H NMR (DMSO-d₆, 300 MHz) δ 2.81 (s, 3H), 6.92-7.02 (m,2H), 7.22 (m, 1H), 8.20 (dd, 1H, J=1.7, 7.8 Hz), 8.27 (s, 1H), 8.65 (s,1H), 9.00 (bs, 2H), 9.41 (bs, 2H), 10.58 (s, 1H); Mass Spectrum (ESI)m/z calcd. for C₁₅H₁₃N₃OS₃, 347.48 (M+H), found 348.2.

EXAMPLE 197 5-Methylthio-4-(6-Quinolylamino)thiophene-2-carboxamidineHydrochloride

a) Methyl 5-methylthio-4-(6-quinolylamino)thiophene-2-carboxylate: To anoven-dried glass vial with stir bar was added a mixture of 65.2 mg(0.244 mmol) of methyl 4-bromo-5-methylthiothiophene-2-carboxylate (asprepared in Example 241, step (a)), 5.2 mg (9.5 mol %) of palladium (II)acetate, 22.2 mg (14.6 mol %) ofracemic-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP), 125 mg(0.384 mmol) of cesium carbonate and 50.3 mg (0.349 mmol) of6-aminoquinoline. The vial was transferred to a glove bag, flushed withdry argon and anhydrous toluene (488 μL) was added. The vial was cappedwith a Teflon-lined screw cap and heated at 100° C. for 48 h. To thecooled suspension was added ethyl acetate (4 mL), the mixture filtered(Celite), washing with ethyl acetate (2×2 mL), and the solvents removedin vacuo. The resulting residue was purified by chromatography on a 10-gsilica SPE column with a gradient of 5-12% ethyl acetate-CH₂Cl₂ toafford 53.3 mg (66%) of the title compound as a pale yellow resin.¹H-NMR (CDCl₃, 400 MHz) δ 8.77 (dd, 1H, J=4.2, 1.6 Hz), 8.04 (d, 1H,J=9.4 Hz), 8.02 (d, 1H, J=8.4 Hz), 7.90 (s, 1H), 7.41 (dd, 1H, J=9.0,2.6 Hz), 7.36 (dd, 1H, J=8.3, 4.2 Hz), 7.27 (d, 1H, J=2.6 Hz), 3.92 (s,3H) and 2.45 (s, 3H). Mass spectrum (ESI, m/z): Calcd. For C₁₆H₁₅N₂O₂S₂,331.1 (M+H), found 331.2.

b) 5-Methylthio-4-(6-quinolylamino)thiophene-2-carboxamidinehydrochloride: Trimethylaluminum (2.0 M in toluene, 0.76 mL, 1.52 mmol)was added dropwise to a suspension of ammonium chloride (85.6 mg, 1.60mmol) in anhydrous toluene (0.76 mL) under Ar at 0° C. The mixture wasstirred at 25° C. for 30 min and then 50.2 mg (0.152 mmol) of methyl5-methylthio-4-(6-quinolylamino)thiophene-2-carboxylate (as prepared inprevious step) was added. The reaction mixture was heated slowly to 100°C. and stirred for 4 h. The cooled mixture was added to a vigorouslystirred slurry of silica gel (3 g) in chloroform (15 mL). The suspensionwas filtered (Celite) washing with 25% MeOH—CH₂Cl₂ (2×5 mL), 50%MeOH—CH₂Cl₂ (2×5 mL) and 75% MeOH—CH₂Cl₂ (2×5 mL). The combined washingswere concentrated and the resulting residue was purified on a 5-g silicaSPE column with a gradient of 10-15% MeOH—CH₂Cl₂ to afford 42.2 mg (79%)of the title compound as a yellow solid. ¹H-NMR (DMSO-d₆, 400 MHz) δ9.39 (br s, 2H), 9.12 (br s, 2H), 8.63 (dd, 1H, J=4.2, 1.6 Hz), 8.44 (s,1H), 8.16 (m, 2H), 7.89 (d, 1H, J=8.5 Hz), 7.54 (dd, 1H, J=9.1, 2.6Hz),7.39 (dd, 1H, J=8.3, 4.2 Hz), 7.20 (d, 1H, J=2.5 Hz) and 2.55 (s, 3H).Mass spectrum (ESI, m/z): Calcd. For C₁₅H₁₄N₄S₂, 315.1 (M+H), found315.2.

EXAMPLE 1985-Methylthio-4-[(3-phenylphenyl)amino]thiphene-2-carboxamidineHydrochloride

a) Methyl 5-methylthio-4-[(3-phenylphenyl)amino]thiophene-2-carboxylate:The same procedure as in Example 197, step (a), was followed using 62.2mg (0.233 mmol) of methyl 4-bromo-5-methylthiothiophene-2-carboxylate(as prepared in Example 241, step (a)), 4.7 mg (9.0 mol %) of palladium(II) acetate, 20.0 mg (13.8 mol %) of racemic-BINAP, 140 mg (0.430 mmol)of cesium carbonate, 48.2 mg (0.285 mmol) of 3-aminobiphenyl and 466 μLof toluene, and chromotographed as before using 20-40% CH₂Cl₂-hexane toafford 52.3 mg (63%) of the title compound as a yellow resin. ¹H-NMR(CDCl₃, 400 MHz) δ 7.81 (s, 1H), 7.61 (m, 2H), 7.46 (m, 2H), 7.38 (m,2H), 7.21 (m, 2H), 7.03 (m, 1H), 6.22 (s, 1H), 3.90 (s, 3H), 2.43 (s,3H). Mass spectrum (ESI, m/z): Calcd. For C₁₉H₁₇NO₂S₂, 356.1 (M+H),found 356.2.

b) 5-Methylthio-4-[(3-phenylphenyl)amino]thiophene-2-carboxamidinehydrochloride: The same procedure as in Example 197 step (b) wasfollowed using 46.4 mg (0.131 mmol) of methyl5-methylthio-4-[(3-phenylphenyl)amino]thiophene-2-carboxylate (asprepared in previous step), 0.76 mL of trimethylaluminum (2.0 M intoluene, 1.57 mmol). 87.7 mg of ammonium chloride (1.64 mmol) and 0.79mL of toluene, and purified on a 5-g silica SPE column with 5-10%MeOH—CH₂Cl₂ to afford 46.8 mg (95%) of the title compound as a yellowfoam. ¹H-NMR (DMSO-d₆, 400 MHz) δ 9.04 (br s, 4H), 8.10 (s, 1H), 8.06(s, 1H), 7.62 (m, 2H), 7.46 (m, 2H), 7.35 (m, 2H), 7.19 (t, 1H,J=1.9Hz), 7.12 (d, 1H, J=8.2Hz), 6.95 (dd, 1H, J=7.8, 1.9 Hz), 2.53 (s,3H). Mass spectrum (ESI, m/z): Calcd. For C₁₈H₁₇N₃S₂, 340.1 (M+H), found340.2.

EXAMPLE 199 5-Methylthio-4-(3-quinolylamino)thiophene-2-carboxamidineHydrochloride

a) Methyl 5-methylthio-4-(3-quinolylamino)thiophene-2-carboxylate: Thesame procedure as in Example 197, step (a) was followed using 104 mg(0.389 mmol) of methyl 4-bromo-5-methylthiothiophene-2-carboxylate (asprepared in Example 241, step (a)), 7.1 mg (8.1 mol %) of palladium (II)acetate, 29.3 mg (12.1 mol%) of racemic-BINAP, 192 mg (0.589 mmol) ofcesium carbonate, 70.5 mg (0.489 mmol) of 3-aminoquinoline and 778 μL oftoluene, and chromatographed as before using 3-8% ethyl acetate-CH₂Cl₂to afford 34.4 mg (27%) of the title compound as a yellow resin. ¹H-NMR(CDCl₃, 400 MHz) δ 8.73 (d, 1H, J=2.5 Hz), 8.04 (d, 1H, J=8.2 Hz), 7.85(d, 1H, J=4.0 Hz), 7.71 (d, 1H, J=7.9 Hz), 7.62 (m, 1H), 7.56 (m, 2H),6.34 (s, 1H), 3.93 (s, 3H) and 2.46 (s, 3H). Mass spectrum (ESI, m/z):Calcd. For C₁₆H₁₄N₂O₂S₂, 331.1 (M+H), found 331.3.

b) 5-Methylthio-4-(3-quinolylamino)thiophene-2-carboxamidinehydrochloride: The same procedures as in Example 197, step (b) wasfollowed using 32.3 mg (0.0977 mmol) of methyl5-methylthio-4-(3-quinolylamino)thiophene-2-carboxylate (as prepared inprevious step), 0.586 mL of trimethylaluminum (2.0 M in toluene, 1.17mmol) and 65.8 mg of ammonium chloride (1.26 mmol) and 0.59 mL oftoluene and purified on a 5-g silica SPE column with 5-12% MeOH—CH₂CH₂to afford, after concentration once from MeOH—MeCN (1:1), 17.3 mg (51%)of the title compound as a light tan crystalline solid. ¹H-NMR (DMSO-d₆,400 MHz) δ 9.09 (br s, 4H), 8.79 (s, 1H), 8.56 (s, 1H), 8.12 (s, 1H),7.89 (m, 1H), 7.79 (m, 1H), 7.56 (s, 1H), 7.50 (m, 2H) and 2.55 (s, 3H).Mass spectrum (ESI, m/z): Calcd. for C₁₅H₁₄N₄S₂, 315.1 (M+H), found315.4.

EXAMPLE 2005-Methylthio-4-(pyrimidin-2-ylamino)thiophene-2-carboxamidineHydrochloride

a) Methyl 5-methylthio-4-(pyrimidin-2-ylamino)thiophene-2-carboxylate:The same procedure as in Example 197, step (a) was followed using 50.9mg (0.191 mmol) of methyl 4-bromo-5-methylthiothiophene-2-carboxylate(as prepared in Example 241, step (a)), 2.7 mg (6.3 mol %) of palladium(II) acetate, 11.3 mg (9.5 mol %) of racemic-BINAP, 101 mg (0.310 mmol)of cesium carbonate, 25.9 mg (0.270 mmol) of 2-aminopyrimidine and 381μL of dioxane, and chromatographed as before using 5-10% ethylacetate-hexane to afford 16.7 mg (31%) of the title compound as a yellowcrystalline solid: 1H-NMR (CDC13, 400 MHz) δ 8.72 (s, 1H), 8.49 (d, 1H,J=4.8 Hz), 6.80 (t, 1H, J=4.8 Hz), 3.92 (s, 3H), 2.42 (s, 3H) and 1.28(br s, 2H). Mass spectrum (ESI, m/z): Calcd. for C₁₁H₁₁N₃O₂S₂, 282.0(M+H), found 282.3.

b) 5-Methylthio-4-(pyrimidin-2-ylamino)thiophene-2-carboxamidinehydrochloride: The same procedure as in Example 197 step (b) wasfollowed using 15.2 mg (0.0540 mmol) of methyl5-methylthio-4-(pyrimidin-2-ylamino)thiophene-2-carboxylate (as preparedin previous step), 0.324 mL or trimethylaluminum (2.0 M in toluene,0.648 mmol) and 36.4 mg of ammonium chloride (0.680 mmol) and 0.32 mL oftoluene, and purified on a 2-g silica SPE column with 5-15% MeOH—CH₂Cl₂to afford, after concentration once from MeOH—MeCN (1:10), 11.4 mg (70%)of the title compound as a light yellow crystalline solid. ¹H-NMR(DMSO-d₆, 300 MHz) δ 9.24 (br s, 2H), 8.85 (br s, 2H), 8.45 (d, 1H,J=4.8 Hz), 8.25 (s, 1H), 6.87 (t, 1H, J=4.8 Hz) and 2.53 (s, 3H). Massspectrum (ESI, m/z): Calcd. for C₁₀H₁₁N₅S₂, 266.1 (M+H), found 266.2.

EXAMPLE 2014-[(4-Cyclohexylphenyl)amino]-5-methylthiothiophene-2-carboxamidineHydrochloride

a) Methyl 4-[(4-cyclohexylphenyl)amino]-5-methylthiothiophene-2-carboxylate: The same procedure as in Example 197, step (a) wasfollowed using 122 mg (0.457 mmol) of methyl4-bromo-5-methylthiothiophene-2-carboxylate (as prepared in Example 241,step (a)), 9.9 mg (9.7 mol %) of palladium (II) acetate, 42.3 mg (14.9mol %) of racemic-BINAP, 206 mg (0.632 mmol) of cesium carbonate, 102 mg(0.582 mmol) of 4-cyclohexylaniline and 913 μL of toluene, andchromatographed as before using 20-40% CH₂Cl₂-hexane to afford 73.8 mg(45%) of the title compound as a light green resin: ¹H-NMR (CDCl₃, 400MHz) δ 7.74 (s, 1H), 7.15 (d, 2H, J=8.4 Hz), 6.98 (d, 2H, J=8.4 Hz),6.12 (s, 1H), 3.88 (s, 3H), 2.48 (m, 1H), 2.39 (s, 3H), 1.87 (m, 4H),1.76 (br d, 1H, J=12.5 Hz), 1.41 (m, 4H) and 1.28 (m, 1H). Mass spectrum(ESI, m/z): Calcd. for C₁₉H₂₃NO₂S₂, 362.1 (M+H), found 362.4.

b) 4-[(4-Cyclohexylphenyl)amino]-5-methylthiothiophene-2-carboxamidinehydrochloride: The same procedure as in Example 197 step (b) wasfollowed using 70.2 mg (0.194 mmol) of methyl4-[(4-cyclohexylphenyl)amino]-5-methylthiothiophene-2-carboxylate (asprepared in previous step), 0.970 mL or trimethylaluminum (2.0 M intoluene, 1.94 mmol), 109 mg of ammonium chloride (2.04 mmol) and 0.97 mLof toluene, and purified on a 10-g silica SPE column with 4-8%MeOH—CH₂Cl₂ to afford 57.7 mg (78%) of the title compound as a yellowfoam. ¹H-NMR (DMSO-d₆, 400 MHz) δ 8.45 (br s, 4H), 7.97 (s, 1H), 7.86(s, 1H), 7.08 (d, 2H, J=8.5 Hz), 6.92 (d, 2H, J=8.5 Hz), 2.48 (s, 3H),1.65-1.85 (m, 5H) and 1.35 (m, 5H). Mass spectrum (ESI, m/z): Calcd. forC₁₈H₂₃N₃S₂, 346.1 (M+H), found 346.4.

EXAMPLE 202 Methyl 4-amino-5-methylthiothiophene-2-carboxylate

To a pressure tube (Ace Glass, Vineland, N.J.) containing 1.0 g (4.30mmol) of 5-(methoxycarbonyl)-2-methylthiothiophene-3-carboxylic acid (asprepared in Example 95), 1.01 mL (1.1 equiv, 4.73 mmol) ofdiphenylphosphoryl azide, and 1.57 mL (2.1 equiv, 9.03 mmol) ofN,N-diisopropylethylamine was charged 7 mL of t-butanol. The resultantmixture was sealed and heated to 80° C. in an oil bath for 6 h. The darkreaction mixture was cooled to ambient temperature and concentrated invacuo. The crude oil was dissolved in 3 mL of CH₂Cl₂ and then treatedwith 2 mL of 1:1 CH₂Cl₂-trifluoroacetic acid followed by 0.5 mL H₂O.After 6 h, the mixture was concentrated in vacuo, dissolved in 50 mL ofCH₂Cl₂, washed with sat'd. NaHCO₃, dried (Na₂SO₄), and eluted through apad of silica gel with 50% ethyl acetate-hexanes. The solvent wasconcentrated in vacuo and the crude amine was purified by preparativethin layer chromatography (20% ethyl acetate-hexanes, 2000 μm SiO₂ gel)to yield 210 mg (24%) of methyl4-amino-5-methylthiothiophene-2-carboxylate as a honey-colored oil. ¹HNMR (DMSO-d₆, 300 MHz) δ 2.28 (s, 3H), 3.77 (s, 3H), 5.36 (bs, 2H), 7.24(s, 1H). Mass spectrum (ESI, m/z): Calcd. for C₇H₉NO₂S₂, 204.02 (M+M),found 204.0.

EXAMPLE 203 Methyl4-[(aminothioxomethyl)amino]-5-methylthiothiophene-2-carboxylate

To a stirring 5 mL biphasic CH₂Cl₂—NaHCO₃ (1:1, v/v) mixture of 98 mg(0.48 mmol) of methyl 4-amino-5-methylthiothiophene-2-carboxylate wasadded 43 μL (1.2 equiv, 0.57 mmol) of thiophosgene (Aldrich Chemical,Milwaukee, Wis.). The reaction was stirred vigorously overnight, dilutedwith CH₂Cl₂ (50 mL), and the layers separated. The organic layer waswashed with NaHCO₃ (1×15 mL), brine (1×15mL), and dried (Na₂SO₄).Concentration of the solvent in vacuo yielded the crude isothiocyanate,which was dissolved in 5 mL of 2M NH₃ in MeOH and stirred overnight. Thereaction was concentrated to ½ volume and filtered. The filtered solidswere washed with acetone and dried, yielding 79.8 mg (63.4%) of methyl4-[(aminothioxomethyl)amino]-5-methylthiothiophene-2-carboxylate as alight tan solid. ¹H NMR (DMSO-d₆, 300 MHz) δ 2.51 (s, 3H), 3.81 (s, 3H),7.41 (bs, 2H), 8.03 (s, 1H) and 9.27 (bs, 1H). Mass spectrum (ESI, m/z):Calcd. for C₈H₁₀N₂O₂S₃, 263.00 (M+H), found 263.2.

EXAMPLE 2045-Methylthio-4-[(4-Phenyl(1,3-thiazol-2-yl))amino]thiophene-2-carboxamidine

a) Methyl5-methylthio-4-[(4-phenyl(1,3-thiazol-2-yl)amino]thiophene-2-carboxylate:To a 25-mL round bottom flask containing 40 mg (0.15 mmol) of methyl4-[(aminothioxomethyl)amino]-5-methylthiothiophene-2-carboxylate and30.3 mg (1 equiv, 0.15 mmol) of bromoacetophenone was added 2 mL ofacetone, and the resultant mixture was heated to reflux for 18 h. Thereaction was cooled to room temperature and filtered to give 50 mg (92%)of methyl5-methylthio-4-[(4-phenyl(1,3-thiazol-2-yl))amino]thiophene-2-carboxylate,which was used without further purification. ¹H NMR (DMSO-d₆, 300 MHz) δ2.49 (s, 3H), 3.84 (s, 3H), 7.09 (s, 1H), 7.26-7.48 (m, 3H), 7.85 (m,2H), 8.63 (s, 1H), 10.06 (bs, 1H). Mass spectrum (ESI, m/z): Calcd. forC₁₆H₁₄N₂O₂S₃, 363.03 (M+H), found 363.4.

b)5-Methylthio-4-[(4-phenyl(1,3-thiazol-2-yl)amino]thiophene-2-carboxamidine:Using a procedure similar to that of Example 154, step (b), 47 mg (0.13mmol) of methyl5-methylthio-4-[(4-phenyl(1,3-thiazol-2-yl))amino]thiophene-2-carboxylatewas allowed to react with 0.5 mL (8 equiv, 1.04 mmol) of the AlMe₃/NH₄Clreagent and purified by preparative thin layer chromatography (20%MeOH—CHCl₃-sat'd. NH₃, 500 μm SiO₂ gel plate) to give 19 mg (42%) of5-methylthio-4-[(4-phenyl(1,3-thiazol-2-yl))amino]thiophene-2-carboxamidineas a yellow solid. ¹H NMR (DMSO-d₆, 300 MHz) δ 2.43 (s, 3H), 7.27-7.42(m, 4H), 7.90 (d, 2H, J=7.1 Hz), 8.41 (s, 1H). Mass spectrum (ESI, m/z):Calcd. for C₁₅H₁₄N₄S3, 347.05 (M+H), found 347.1.

EXAMPLE 2055-Methylthio-4-{[4-(4-phenylphenyl)(1,3-thiazol-2-yl)]amino}thiophene-2-carboxamidine

a) Methyl5-methylthio-4-{[4-(4-phenylphenyl)(1,3-thiazol-2-yl)]amino}thiophene-2-carboxylate:Using a procedure similar to Example 204, step (a) 53 mg (0.2 mmol) ofmethyl 4[(aminothioxomethyl)amino]-5-methylthiothiophene-2-carboxylatewas allowed to react with 55.6 mg (0.2 mmol) of4-phenyl-bromoacetophenone for 3 h to afford 57 mg (65%) of methyl5-methylthio-4-{[4-(4-phenylphenyl)(1,3-thiazol-2-yl)]amino}thiophene-2-carboxylate.¹H NMR (DMSO-d₆, 300 MHz) δ 2.51 (s, 3H), 3.86 (s, 3H), 6.93 (s, 1Hrotomer), 7.10 (s, 1H rotomer), 7.27 (s, 1H rotomer), 7.37-7.50 (m, 3Hrotomer), 7.72-7.76 (m, 4H rotomer), 8.4 (d, 2H, 8.4 Hz), 8.66 (s, 1Hrotomer), 10.10 (bs, 1H). Mass spectrum (ESI, m/z): Calcd. forC₂₂H₁₈N₂O₂S₃, 439.06 (M+H), found 439.2.

b)5-Methylthio-4-{[4-(4-phenylphenyl(1,3-thiazol-2-yl)]amino}thiophene-2-carboxamidine:Using a procedure similar to that of Example 154, step (b), 57 mg (0.12mmol) of methyl5-methylthio-4-{[4-(4-phenylphenyl)(1,3-thiazol-2-yl)]amino}thiophene-2-carboxylatewas allowed to react with 6.7 equiv (0.87 mmol) of the AlMe₃/NH₄Clreagent and purified by preparative thin layer chromatography (20%MeOH—CHCl₃-sat'd. NH₃, 500 μm SiO₂ plate) to give 20.7 mg (40.7%) of5-methylthio-4-{[4-(4-phenylphenyl)(1,3-thiazol-2-yl)]amino}thiophene-2-carboxamidine.¹H NMR (DMSO-d₆, 400 MHz) δ 2.51 (s, 3H), 6.93 (s, 1H), 7.10 (s, 1H),7.27 (s, 1H), 7.35-7.50 (m, 4H), 7.72-7.76 (m, 4H), 7.94-7.96 (m, 2H),8.66 (s, 1H), 10.11 (bs, 1H). Mass spectrum (ESI, m/z): Calcd. forC₂₁H₁₈N₄S₃, 423.08 (M+H), found 423.2.

EXAMPLE 2064-[(5-Methyl-4-phenyl(1,3-thiazol-2-yl))amino]-5-methylthiothiophene-2-carboxamidine

a)Methyl-4-[(5-methyl-4-phenyl(1,3-thiazol-2-yl)amino]-5-methylthiothiophene-2-carboxylate:Using a procedure similar to Example 204, step (a), 51 mg (0.19 mmol) ofmethyl 4-[(aminothioxomethyl)amino]-5-methylthiothiophene-2-carboxylatewas allowed to react with 41.4 mg (0.38 mmol) of 2-bromopropiophenone(Aldrich Chemical Co., Milwaukee, Wis.) in 2 mL of DMF for 4 h.Concentration in vacuo of the reaction mixture afforded 73 mg (100%) ofmethyl-4-[(5-methyl-4-phenyl(1,3-thiazol-2-yl))amino]-5-methylthiothiophene-2-carboxylate.Mass spectrum (ESI, m/z): Calcd. for C₁₇H₁₆N₂O₂S₃, 377.05 (M+H), found377.2.

b)4-[(5-Methyl-4-phenyl(1,3-thiazol-2-yl))amino]-5-methylthiothiophene-2-carboxamidine:Using a procedure similar to Example 154, step (b), 73 mg (0.19 mmol) ofmethyl-4-[(5-methyl-4-phenyl(1,3-thiazol-2-yl))amino]-5-methylthiothiophene-2-carboxylatewas allowed to react with 8 equiv (1.5 mmol) of the AlMe₃/NH₄Cl reagentand purified by preparative thin layer chromatography(20%-MeOH—CHCl₃-sat'd. NH₃, 500 μm SiO₂ plate) to afford 17.9 mg (26%)of4-[(5-methyl-4-phenyl(1,3-thiazol-2-yl))amino]-5-methylthiothiophene-2-carboxamidine.¹H NMR (DMSO-d₆, 300 MHz): δ 2.40 (s, 3H), 2.51 (s, 3H rotomer), 2.73(s, 3H rotomer), 7.29-7.44 (m, 2H rotomer), 7.64-7.73 (m, 3H rotomer),7.95 (s, 1H rotomer), 8.06 (s, 1H rotomer). Mass spectrum (ESI, m/z):Calcd. for C₁₆H₁₆N₄S₃, 361.06 (M+H), found 361.2.

EXAMPLE 2074-{[4-Hydroxy-4-(trifluoromethyl)(1,3-thiazolin-2-yl)]amino}-5-methylthiothiophene-2-carboxamidine

a) Methyl4-{[4-hydroxy-4-(trifluoromethyl)(1,3-thiazolin-2-yl)]amino}-5-methylthiothiophene-2-carboxylate:Using a procedure similar to Example 204, step (a), 56 mg (0.21 mmol) ofmethyl 4-[(aminothioxomethyl)amino]-5-methylthiothiophene-2-carboxylatewas allowed to react with 40 mg (0.21 mmol) of bromotrifluoroacetone(Aldrich Chemical Co., Milwaukee, Wis.) to afford 40.3 mg (54%) ofmethyl4-{[4-hydroxy-4-(trifluoromethyl)(1,3-thiazolin-2-yl)]amino}-5-methylthiothiophene-2-carboxylate.Mass spectrum (ESI, m/z): Calcd. for C₁₁H₁₁F₃N₂O₃S₃, 373.00 (M+H), found373.0.

b)4-{[4-Hydroxy-4-(trifluoromethyl)(1,3-thiazolin-2-yl)]amino}-5-methylthiothiophene-2-carboxamidine:Using a procedure similar to Example 154, step (b), 40 mg (0.11 mmol) ofmethyl4-{[4-hydroxy-4-(trifluoromethyl)(1,3-thiazolin-2-yl)]amino}-5-methylthiothiophene-2-carboxylatewas allowed to react with 8 equiv (0.89 mmol) of the AlMe₃/NH₄Cl reagentand purified by preparative thin layer chromatography20%-MeOH—CHCl₃-sat'd. NH₃, 500 μm SiO₂ plate) to afford 11 mg (28%) of4-{[4-hydroxy-4-(trifluoromethyl)(1,3-thiazolin-2-yl)]amino}-5-methylthiothiophene-2-carboxamidineas a ca. 1:1 mixture of cyclized aminal and open imine tautomers. ¹H NMR(DMSO-d₆, 300 MHz) δ 2.73 (s, 3H tautomer), 2.89 (s, 3H tautomer), 3.36(d, 2H, J=6.5 Hz), 3.62 (d, 2H, J=7.2 Hz), 7.95 (s, 1H), 8.36 (bs, 2H),9.79 (bs, 1H). Mass spectrum (ESI, m/z): Calcd. for C₁₀H₁₁F₃N₄OS₃,357.01 (M+H), found 357.2.

EXAMPLE 208 5-Methylthio-4-(2-naphthylamino)thiophene-2-carboxamidine

a) Methyl 5-methylthio-4-(2-naphthylamino)thiophene-2-carboxylate: To anoven-dried round bottom flask equipped with Teflon-coated stir bar andrubber septum was added 190 mg (0.93 mmol) of methyl4-amino-5-methylthiothiophene-2-carboxylate, 320 mg (2 equiv, 1.86 mmol)of 2-napthalene boronic acid (Lancaster Synthesis, Windham, N.H.), and168 mg (1 equiv, 0.93 mmol) of Cu(OAc)₂ (Aldrich Chemical Co.,Milwaukee, Wis.). The flask was flushed with Ar, then charged with 4 mLCH₂Cl₂ followed by 259 μL (2 equiv, 1.86 mmol) of NEt₃. The mixture wasstirred vigorously for 48 h and then filtered through a small pad ofSiO₂, eluting with 50% ethyl acetate-hexanes. Concentration of thesolvent in vacuo, and purification of the residue by preparative thinlayer chromatography (25% ethyl acetate-hexanes, 1000 μM SiO₂ plate)afforded 170 mg (55%) of methyl5-methylthio-4-(2-naphthylamino)thiophene-2-carboxylate and 54 mg (28%)of recovered methyl 4-amino-5-methylthiothiophene-2-carboxylate. ¹H NMR(CDCl₃, 400 MHz) δ 2.43 (s, 3H), 3.92 (s, 3H), 6.29 (s, 1H), 7.21 (dd,1H, J=2.35, 8.7 Hz), 7.33-7.37 (m, 2H), 7.45 (m, 1H), 7.71 (d, 1H, J=8.2Hz), 7.78 (m, 2H), 7.88 (s, 11H). Mass spectrum (ESI, m/z): Calcd. forC₁₇H₁₅NO₂S₂, 330.06 (M+H), found 330.1.

b) 5-Methylthio-4-(2-naphthylamino)thiophene-2-carboxamidinehydrochloride: Using a procedure similar to Example 154, step(b), 730 mg(2.21 mmol) of methyl5-methylthio-4-(2-naphthylamino)thiophene-2-carboxylate was allowed toreact with 8 equiv (17.7 mmol) of the AlMe₃/NH₄Cl reagent and purifiedby preparative thin layer chromatography (20%-MeOH—CHCl₃-sat'd. NH₃,1000 μm SiO₂ plate) to afford5-methylthio-4-(2-naphthylamino)thiophene-2-carboxamidine, which wasdissolved in 4 mL of dry MeOH, cooled to 0° C. and carefully treatedwith 1.6 mL(1.5 equiv, 3.31 mmol) of 2M HCl in ether. The reaction wasstored at 5° C. overnight, then concentrated in vacuo with toluene (3×10mL) and then hexanes (2×10 mL). The yellow solid was dried under vacuumto afford 415 mg (53.6%) of5-methylthio-4-(2-naphthylamino)thiophene-2-carboxamidine hydrochloride.¹H NMR (DMSO-d₆, 400 MHz) δ 2.53 (s, 3H), 7.20 (d, 1H, J=2.2 Hz),7.24-7.31 (m, 2H), 7.38 (m, 1H), 7.69 (d, 1H, 8.1 Hz), 7.75-7.79 (m,2H), 8.13 (s, 1H), 8.24 (s, 1H), 9.06 (bs, 2H), 9.33 (bs, 2H). Massspectrum (ESI, m/z): Calcd. for C₁₆H₁₅N₃S₂, 314.08 (M+H), found 314.5.

EXAMPLE 2094-[(4-Chlorophenyl)amino]-5-methylthiothiophene-2-carboxamidine

a) Methyl 4-[(4-chlorophenyl)amino]-5-methylthiothiophene-2-carboxylate:Using a procedure similar to Example 208, step (a), 66.6 mg (0.32 mmol)of methyl 4-amino-5-methylthiothiophene-2-carboxylate was allowed toreact with 100 mg (2 equiv, 0.64 mmol) of 4-chlorophenyl boronic acid togive 11.8 mg (11.7%) of methyl4-[(4-chlorophenyl)amino]-5-methylthiothiophene-2-carboxylate and 21 mg(31.5%) of unreacted starting material. ¹H NMR (CDCl₃, 400 MHz) δ 2.41(s, 3H), 3.89 (s, 3H), 6.09 (bs, 1H), 6.94 (d, 2H, J=8.6 Hz), 7.25 (d,2H, J=8.6 Hz), 7.70 (s, 1H).

b) 4-[(4-chlorophenyl)amino]-5-methylthiothiophene-2-carboxamidinehydrochloride: Using a procedure similar to Example 154, step (b), 11.8mg (0.037 mmol) of methyl4-[(4-chlorophenyl)amino]-5-methylthiothiophene-2-carboxylate wasallowed to react with 8 equiv (2.96 mmol) of the AlMe₃/NH₄Cl reagent toafford 13 mg (100%) of4-[(4-chlorophenyl)amino]-5-methylthiothiophene-2-carboxamidine. ¹H NMR(DMSO-d₆, 400 MHz) δ 2.41 (s, 3H), 6.91-6.95 (m, 2H) 7.10-7.13 (m, 2H),7.64 (s, 1H), 7.93 (s, 1H), 8.67 (bs, 2H), 9.11 (bs, 2H). Mass spectrum(ESI, m/z): Calcd. for C₁₂H₁₂ClN₃S₂, 298.02 (M+H), found 298. 1.

EXAMPLE 2104-[(3-Methylphenyl)amino]-5-methylthiothiophene-2-carboxamidine

a) Methyl 4-[(3-methylphenyl)amino]-5-methylthiothiophene-2-carboxylate:Using a procedure similar to Example 208, step (a), 55.7 mg (0.27 mmol)of methyl 4-amino-5-methylthiothiophene-2-carboxylate was allowed toreact with 73.4 mg (2 equiv, 0.54 mmol) of 3-methylphenyl boronic acidto give 29.2 mg (36.8%) of methyl4-[(3-methyl)amino]-5-methylthiothiophene-2-carboxylate. ¹H NMR (CDCl₃,400 MHz) δ 2.35 (s, 3H), 2.40 (s, 3H), 3.89 (s, 3H), 6.11 (bs, 1H),6.80-6.86 (m, 3H), 7.20 (m, 1H), 7.77 (s, 1H). Mass spectrum (ESI, m/z):Calcd. for C₁₄H₁₅NO₂S₂, 294.06 (M+H), found 294. 1.

b) 4-[(3-methylphenyl)amino]-5-methylthiothiophene-2-carboxamidine:Using a procedure similar to Example 154, step (b), 29.2 mg (0.098 mmol)of methyl 4-[(3-methyl)amino]-5-methylthiothiophene-2-carboxylate wasallowed to react with 8 equiv (0.78 mmol) of the AlMe₃/NHCl reagent andpurified by preparative thin layer chromatography (20%-MeOH—CHCl₃-sat'd.NH₃, 500 μm SiO₂ plate) to afford 27 mg (100%) of4-[(3-methylphenyl)amino]-5-methylthiothiophene-2-carboxamidine. ¹H NMR(CDCl₃, 400 MHz) δ 2.24 (s, 3H), 2.50 (s, 3H), 6.65 (d, 1H, J=7.3 Hz),6.74-6.76 (m, 2H), 7.10 (m, 1H), 7.88 (s, 1H), 7.97 (s, 1H), 9.07 (bs,3H). Mass spectrum (ESI, m/z): Calcd. for C₁₃H₁₅N₃S₂, 278.08 (M+H),found 278.2.

EXAMPLE 2114-[(3-Methoxyphenyl)amino]-5-methylthiothiophene-2-carboxamidine

a)Methyl-4-[(3-methoxyphenyl)amino]-5-methylthiothiophene-2-carboxylate:Using a procedure similar to Example 208, step (a), 73.2 mg (0.35 mmol)of methyl 4-amino-5-methylthiothiophene-2-carboxylate was allowed toreact with 109 mg (2 equiv, 0.70 mmol) of 3-methoxyphenyl boronic acidto give 25.2 mg (23%) of methyl4-[(3-methoxyphenyl)amino]-5-methylthiothiophene-2-carboxylate. ¹H NMR(CDCl₃, 400 MHz) δ 2.40 (s,3H), 3.81 (s, 3H), 3.89 (s, 3H), 6.12 (s,1H), 6.43-6.63 (m, 2H), 7.20 (m, 1H), 7.78 (s, 1H). Mass spectrum (ESI,m/z): Calcd. for C₁₄H₁₅NO₃S₂, 310.06 (M+H), found 310.1.

b) 4-[(3-Methylphenyl)amino]-5-methylthiothiophene-2-carboxamidinehydrochloride: Using a procedure similar to Example 154, step (b), 25.2mg (0.081 mmol) of methyl4-[(3-methyl)amino]-5-methylthiothiophene-2-carboxylate was allowed toreact, with 8 equiv (0.64 mmol) of the AlMe₃/NH₄Cl reagent to afford 27mg (100%) of4-[(3-methoxyphenyl)amino]-5-methylthiothiophene-2-carboxamidine. ¹H NMR(DMSO, 400 MHz) δ 2.49 (s, 3H), 3.71 (s, 3H), 6.41 (dd, 1H, J=2.1, 8.0Hz), 6.49 (m, 1H), 6.50-6.54 (m, 1H), 7.12 (m, 1H), 7.97 (s, 1H), 8.01(s, 1H), 8.88 (bs, 2H), 9.23 (bs, 2H). Mass spectrum (ESI, m/z): Calcd.for C₁₃H₁₅N₃OS₂, 294.07 (M+H), found 294.1.

EXAMPLE 2124-{[3-(Methylethyl)phenyl]amino}-5methylthiothiophene-2-carboxamidine

a) Methyl4-{[3-(methylethyl)phenyl]amino}-5-methylthiothiophene-2-carboxylate:Using a procedure similar to Example 208, step (a), 74.4 mg (0.36 mmol)of methyl 4-amino-5-methylthiothiophene-2-carboxylate was allowed toreact with 118 mg (2 equiv, 0.72 mmol) of 3-isopropylphenyl boronic acidto give 22.6 mg (19.5%) of methyl4-[(3-methylethylphenyl)amino]-5-methylthiothiophene-2-carboxylate. ¹HNMR (CDCl₃, 400 MHz) δ 1.27 (d, 6H, J=6.9 Hz), 2.40 (s, 3H), 2.89 (m,1H), 3.88 (s, 3H), 6.15 (s, 1H), 6.86-6.89 (m, 3H), 7.24 (m, 1H), 7.77(s, 1H).

b)4-{[3-(Methylethyl)phenyl]amino}-5-methylthiothiophene-2-carboxamidine:Using a procedure similar to Example 154, step (b), 22.6 mg (0.07 mmol)of methyl4-{[3-(methylethyl)phenyl]amino}-5-methylthiothiophene-2-carboxylate wasallowed to react with 8 equiv (0.56 mmol) of the AlMe₃NH₄Cl reagent toafford 18.9 mg (78.8%) of)4-{[3-(methylethyl)phenyl]amino}-5-methylthiothiophene-2-carboxamidine.¹H NMR (DMSO-d₆, 400 MHz) δ 1.18 (d, 6H, J=9.2 Hz), 2.51 (s, 3H), 2.81(m, 1H), 6.71-6.77 (m, 2H), 6.85 (s, 1H), 7.14 (m, 1H), 7.98 (s, 1H),8.32 (s, 1H), 8.88 (bs, 2H), 9.23 (bs, 2H). Mass spectrum (ESI, m/z):Calcd. for C₁₅H₁₉N₃S₂, 306.11 (M+H), found 306.2.

EXAMPLE 2135-Methylthio-4-[(3-nitrophenyl)amino]thiophene-2-carboxamidine

a) Methyl 5-methylthio-4-[(3-nitrophenyl)amino]thiophene-2-carboxylate:Using a procedure similar to Example 208, step (a), 74.4 mg (0.36 mmol)of methyl 4-amino-5-methylthiothiophene-2-carboxylate was allowed toreact with 120 mg (2 equiv, 0.72 mmol) of 3-nitrophenyl boronic acid togive 14.5 mg (12.4%) of methyl5-methylthio-4-[(3-nitrophenyl)amino]thiophene-2-carboxylate. ¹H NMR(CDCl₃, 400 MHz) δ 2.45 (s, 3H), 3.93 (s, 3H), 6.21 (s, 1H), 7.41-7.47(m, 2H), 7.73-7.78 (m, 3H).

b) 5-Methylthio-4-[(3-nitrophenyl)amino]thiophene-2-carboxamidine: Usinga procedure similar to Example 154, step (b), 14.5 mg (0.04 mmol) ofmethyl 5-methylthio-4-[(3-nitrophenyl)amino]thiophene-2-carboxylate wasallowed to react with 8 equiv (0.35 mmol) of the AlMe₃/NH₄Cl reagent toafford 4.3 mg (34.8%) of5-methylthio-4-[(3-nitrophenyl)amino]thiophene-2-carboxamidine. Massspectrum (ESI, m/z): Calcd. for C₁₂H₁₂N₄O₂S₂, 309.05 (M+H), found 309.2.

EXAMPLE 2144-{[4-(Methylethyl)phenyl]amino}-5-methylthiothiophene-2-carboxamidine

a) Methyl4-{[4-(methylethyl)phenyl]amino}-5-methylthiothiophene-2-carboxylate:Using a procedure similar to Example 208, step (a), 74.4 mg (0.36 mmol)of methyl 4-amino-5-methylthiothiophene-2-carboxylate was allowed toreact with 118 mg (2 equiv, 0.72 mmol) of 4-isopropylphenyl boronic acidto give 14.5 mg (12.5%) of methyl4-[(4-methylethylphenyl)amino]-5-methylthiothiophene-2-carboxylate. ¹HNMR (CDCl₃, 400 MHz) δ 1.26 (d, 6H, J=6.2 Hz), 2.39 (s, 3H), 2.89 (m,1H), 3.89 (s, 3H), 6.98-7.01 (m, 2H), 7.17-7.19 (m, 2H), 7.73 (s, 1H).

b)4-{[4-(Methylethyl)phenyl]amino}-5-methylthiothiophene-2-carboxamidine:Using a procedure similar to Example 154, step (b), 14.5 mg (0.045 mmol)of methyl4-{[4-(methylethyl)phenyl]amino}-5-methylthiothiophene-2-carboxylate wasallowed to react with 8 equiv (0.36 mmol) of the AlMe₃/NH₄Cl reagent toafford 11.4 mg (74%) of4-{[4-(methylethyl)phenyl]amino}-5-methylthiothiophene-2-carboxamidine.¹H NMR (DMSO-d₆, 400 MHz) δ 1.17 (d, 6H, J=9.2 Hz), 2.51 (s, 3H), 2.81(m, 1H), 6.92 (d, 2H, J=11.4 Hz), 7.10 (d, 2H, J=11.2 Hz), 7.88 (s, 1H),7.96 (s, 1H), 8.89 (bs, 2H), 9.22 (bs, 2H). Mass spectrum (ESI, m/z):Calcd. for C₁₅H₁₉N₃S₂, 306.11 (M+H), found 306.2.

EXAMPLE 215

4-[(3,4-Dimethylphenyl)amino]-5-methylthiothiophene-2-carboxamidine

a) Methyl4-[(3,4-dimethylphenyl)amino]-5-methylthiothiophene-2-carboxylate: Usinga procedure similar to Example 208, step (a), 74.4 mg (0.36 mmol) ofmethyl 4-amino-5-methylthiothiophene-2-carboxylate was allowed to reactwith 108 mg (2 equiv, 0.72 mmol) of 3, 4-dimethylphenyl boronic acid togive 135.9 mg (32.4%) of methyl4-[(3,4-dimethylphenyl)amino]-5-methylthiothiophene-2-carboxylate. ¹HNMR (CDCl₃, 400 MHz) δ 2.24 (s; 3H), 2.26 (s, 3H), 2.38 (s, 3H), 3.88(s, 3H), 6.11 (bs, 1H), 6.80-6.84 (m, 2H), 7.07 (d, 1 H, J=7.9 Hz), 7.71(s, 1H).

b) 4-[(3,4-Dimethylphenyl)amino]-5-methylthiothiophene-2-carboxamidine:Using a procedure similar to Example 154, step (b), 35.6 mg (0.116 mmol)of methyl4-[(3,4-dimethylphenyl)amino]-5-methylthiothiophene-2-carboxylate wasallowed to react with 8 equiv (0.93 mmol) of the AlMe₃/NH₄Cl reagent toafford 26.1 mg (68.5%) of4-[(3,4-dimethylphenyl)amino]-5-methylthiothiophene-2-carboxamidine. ¹HNMR (DMSO-d₆, 400 MHz) δ 2.13 (s, 3H), 2.16 (s, 3H), 2.51 (s, 3H),6.69-6.78 (m, 2H), 6.99 (d, 1H, J=10.8 Hz), 7.76 (s, 1H), 7.91 (s, 1H),8.82 (bs, 2H), 9.17 (bs, 2H). Mass spectrum (ESI, m/z): Calcd. forC₁₄H₁₇N₃S₂, 292.09 (M+H), found 292.2.

EXAMPLE 2165-Methylthio-4-[(4-phenylpenyl)amino]thiophene-2-carboxamidine

a) Methyl 5-methylthio-4-[(4-phenylphenyl)amino]thiophene-2-carboxylate:Using a procedure similar to Example 208, step (a), 74.4 mg (0.36 mmol)of methyl 4-amino-5-methylthiothiophene-2-carboxylate was allowed toreact with 142.5 mg (2 equiv, 0.72 mmol) of 4-phenylphenyl boronic acidto give 24.5 mg (19.1%) of methyl4-[(4-phenylphenyl)amino]-5-methylthiothiophene-2-carboxylate. ¹H NMR(CDCl₃, 400 MHz) δ 2.45 (s, 3H), 3.92 (s, 3H), 6.38 (bs, 1H), 7.08-7.14(m, 2H), 7.33 (m, 1H), 7.43-7.46 (m, 2H), 7.54-7.60 (m, 411), 7.82 (s,1H).

b) 5-Methylthio-4-[(4-phenylphenyl)amino]thiophene-2-carboxamidine:Using a procedure similar to Example 154, step (b), 24.5 mg (0.07 mmol)of methyl 4-[(4-phenylphenyl)amino]-5-methylthiothiophene-2-carboxylatewas allowed to react with 8 equiv (0.56 mmol) of the AlMe₃/NH₄Cl reagentto afford 16.9 mg (64.1%) of5-methylthio-4-[(4-phenylphenyl)amino]thiophene-2-carboxamidine. 1H NMR(DMSO-d₆, 400 MHz) δ 2.51 (s, 3H), 7.03 (d, 2H, J=8.6 Hz), 7.26-7.61 (m,7H), 8.04 (s, 1H), 8.15 (s, 1H), 8.88 (bs, 2H), 9.25 (bs, 2H). Massspectrum (ESI, m/z): Calcd. for C₁₈H₁₇N₃S₂, 340.09 (M+H), found 340.2.

EXAMPLE 2174-[(3-Fluoro-4-phenylphenyl)amino]-5-Methylthiothiophene-2-carboxamidine

a) Methyl4-[(3-fluoro-4-phenylphenyl)amino]-5-methylthiothiophene-2-carboxylate:Using a procedure similar to Example 208, step (a), 74.4 mg (0.36 mmol)of methyl 4-amino-5-methylthiothiophene-2-carboxylate was allowed toreact with 155.5 mg (2 equiv, 0.72 mmol) of 3-fluoro-4-phenylphenylboronic acid to give 50.6 mg (41.6%) of methyl4-[(3-fluoro-4-phenylphenyl)amino]-5-methylthiothiophene-2-carboxylate.¹H NMR (CDCl₃, 400 MHz) δ 2.44 (s, 3H), 3.91 (s, 3H), 6.19 (s, 1H),6.78-6.86 (m, 2H), 7.32-7.39 (m, 2H), 7.73-7.47 (m, 2H), 7.55 (d, 1H,J=6.9 Hz), 7.82 (s, 1H).

b)4-[(3-Fluoro-4-phenylphenyl)amino]-5-methylthiothiophene-2-carboxamidine:Using a procedure similar to Example 154, step (b), 50.6 mg (0.13 mmol)of methyl4-[(3-fluoro-4-phenylphenyl)amino]-5-methylthiothiophene-2-carboxylatewas allowed to react with 8 equiv (1.08 mmol) of the AlMe₃/NH₄Cl reagentto afford 39 mg (76.1%) of4-[(3-fluoro-4-phenylphenyl)amino]-5-methylthiothiophene-2-carboxamidine.¹H NMR (DMSO-d₆, 400 MHz) δ 2.51 (s, 3H), 6.75-6.87 (m, 2H), 7.30-7.50(m, 6H), 8.06 (s, 1H), 8.37 (s, 1H), 8.90 (bs, 2H), 9.27 (bs, 2H). Massspectrum (ESI, m/z): Calcd. for C₁₈H₁₆FN₃S₂, 358.08 (M+H), found 358.2.

EXAMPLE 2184-(2H-Benzo[d]1,3-dioxolen-5-ylamino)-5-methylthiothiophene-2-carboxamidine

a) Methyl4-(2H-benzo[d]1,3-dioxolen-5-methylthiothiophene-2-carboxylate: Using aprocedure similar to Example 208, step (a), 74.4 mg (0.36 mmol) ofmethyl 4-amino-5-methylthiothiophene-2-carboxylate was allowed to reactwith 119.4 mg (2 equiv, 0.72 mmol) of 3,4-methylenedioxyphenyl boronicacid to give 24.4 mg (20.9%) of methyl4-(2H-benzo[d]1,3-dioxolen-5-ylamino)-5-methylthiothiophene-2-carboxylate. ¹H NMR (CDCl₃, 400 MHz) δ 2.39 (s, 3H), 3.87 (s, 3H), 5.96 (s, 2H),6.00 (bs, 1H), 6.52 (dd, 1H, J=2.3, 8.3 Hz), 6.63 (d, 1H, J=2.2 Hz),6.76 (d, 1H, J=8.3 Hz), 7.59 (s, 1H).

b)4-(2H-Benzo[d]1,3-dioxolen-5-ylamino)-5-methylthiothiophene-2-carboxamidine:Using a procedure similar to Example 154, step (b), 24.4 mg (0.075 mmol)of methyl4-(2H-benzo[d]1,3-dioxolen-5-ylamino)-5-methylthiothiophene-2-carboxylatewas allowed to react with 8 equiv (0.6 mmol) of the AlMe₃/NH₄Cl reagentto afford 7.7 mg (29.7%)4-(2H-benzo[d]1,3-dioxolen-5-ylamino)-5-methylthiothiophene-2-carboxamidine.¹H NMR (DMSO-d₆, 400 MHz) δ 2.51 (s, 3H), 5.95 (s, 2H), 6.46 (dd, 1H,J=3.0, 11.2 Hz), 6.65 (d, 1H, J=2.8 Hz), 6.79 (d, 1H. J=11.0 Hz), 7.80(s, 1H), 7.87 (s, 1H), 8.91 (bs, 2H), 9.24 (bs, 2H). Mass spectrum (ESI,m/z): Calcd. for C₁₃H₁₃N₃O₂S₂, 308.05 (M+H), found 308.2.

EXAMPLE 2194-[(4-Butylphenyl)amino]-5-methylthiothiophene-2-carboxamidine

a) Methyl 4-[(4-butylphenyl)amino]-5-methylthiothiophene-2-carboxylate:Using a procedure similar to Example 208, step (a). 74.4 mg (0.36 mmol)of methyl 4-amino-5-methylthiothiophene-2-carboxylate was allowed toreact with 128 mg (2 equiv, 0.72 mmol) of 4-butylphenyl boronic acid togive 22.2 mg (18.3%) of methyl4-[(4-butylphenyl)amino]-5-methylthiothiophene-2-carboxylate. ¹H NMR(CDCl₃, 400 MHz) 5 0.97 (t, 2H, J=7.4 Hz), 1.38 (m, 2H), 1.59 (m, 2Hobscured by water), 2.39 (s, 3H), 2.58 (t, 2H, J=7.6 Hz), 3.90 (s, 3H),6.12 (bs, 1H1), 6.97 (d, 2H, J=8.2 Hz), 7.12 (d, 2H, J=8.4 Hz), 7.73 (s,1H).

b) 4-[(4-Butylphenyl)amino]-5-methylthiothiophene-2-carboxamidine: Usinga procedure similar to Example 154, step (b). 22.2 mg (0.06 mmol) ofmethyl 4-[(4-butylphenyl)amino]-5-methylthiothiophene-2-carboxylate wasallowed to react with 8 equiv (0.52 mmol) of the AlMe₃/NH₄Cl reagent toafford 18.9 mg (88%) of4-[(4-butylphenyl)amino]-5-methylthiothiophene-2-carboxamidine. ¹H NMR(DMSO-d₆, 400 MHz) δ 0.89 (t, 2H, J=9.7 Hz), 1.23-1.33 (m, 2H), 1.51 (m,2H), 2.47-2.50 (m, 2H obscured by DMSO-d₆), 2.51 (s, 3H), 6.90 (d, 2H,J=11.3 Hz), 7.05 (d, 2H, J=11.2 Hz), 7.86 (s, 1H), 7.94 (s, 1H), 8.78(bs, 2H), 9.21 (bs, 2H). Mass spectrum (ESI, m/z): Calcd. forC₁₆H₂₁N₃S₂, 320.13 (M+H), found 320.2.

EXAMPLE 220 5-Methylthio-4-[benzylamino]thiophene-2-carboxamidine

a) Methyl-5-methylthio-4-[benzylamino]thiophene-2-carboxylate: To a2-dram vial equipped with a stir bar and septum cap was weighed 60 mg(0.29 mmol) of methyl 4-amino-5-methylthiothiophene-2-carboxylate and30.7 mg (0.29 mmol) of benzaldehyde. The vial was charged with 1 mLCH₂Cl₂-DMF (2:1, v/v) and 135 mg (2.2 equiv, 0.63 mmol) of NaHB(OAc)₃was added. The reaction was flushed with Ar and allowed to stir for 48h. At this time 2 mL of CH₃OH was added, the reaction stirred anadditional 15 min then diluted with 20 ml of CH₂Cl₂. The organic layerwas washed with water (2×20 mL), dried (Na₂SO₄), and concentrated invacuo into an oven-dried 2 dram vial to give the crudemethyl-5-methylthio-4-[benzylamino]thiophene-2-carboxylate together withunreduced imine. The crude reaction mixture was converted to the amidinewithout further purification. Mass spectrum (ESI, m/z): Calcd. forC₁₄H₁₅NO₂S₂, 294.06 (M+H), found 292.2 (imine), 294.2.

b) 5-Methylthio-4-[benzylamino]thiophene-2-carboxamidine: To a 2-dramvial containing a stir bar andmethyl-5-methylthio-4-[benzylamino]thiophene-2-carboxylate (assume 0.29mmol) was added 2 mL of toluene, followed by 8 equiv (2.32 mmol) of theAlMe₃/NH₄Cl reagent. The resultant yellow mixture was heated to 110° C.for 3 h, cooled to ambient temperature, and then added to a slurry of 1g of SiO₂ gel in 10 mL of CHCl₃. After stirring for 15 min, the slurrywas eluted through a 15-mL sintered glass funnel containing a pad ofsilica gel with 50% CHCl₃—CH₃OH. The solvent was removed in vacuo andthe residue was triturated with 10% CH₃OH—CHCl₃ and filtered. Removal ofthe solvent in vacuo gave the crude product which was purified bypreparative thin layer chromatography (500 μm SiO₂, 20%CH₃OH—CHCl₃-sat'd. NH₃) 14.8 mg (18.3% from methyl4-amino-5-methylthiothiophene-2-carboxylate) of5-methylthio-4-[benzylamino]thiophene-2-carboxamidine. ¹H NMR (DMSO-d₆,400 MHz) δ 2.49 (s, 3H), 4.35 (d, 2H, J=6.7 Hz), 5.91 (t, 1H, J=6.8 Hz),7.20-7.38 (m, 6H). Mass spectrum (ESI, m/z): Calcd. for C₁₃H₁₅N₃S₂,278.08 (M+H), found 278.3.

EXAMPLE 221 4-(Indan-5-ylamino)-5-methylthiothiophene-2-carboxamidine

a) Methyl 4-(indan-5-ylamino)-5-methylthiothiophene-2-carboxylate: Usingthe procedure described in Example 220, step (a), 60 mg (0.29 mmol) ofmethyl 4-amino-5-methylthiothiophene-2-carboxylate, 42.3 mg (0.29 mmol)of 5-indancarboxaldehyde, and 135 mg (2.2 equiv, 0.63 mmol) ofNaHB(OAc)₃ were allowed to react to give methyl4-(indan-5-ylamino)-5-methylthiothiophene-2-carboxylate. Mass spectrum(ESI, m/z): Calcd. for C₁₇H₁₉NO₂S₂, 334.09 (M+H), found 332.3 (imine),333.4.

b) 4-(Indan-5-ylamino)-5-methylthiothiophene-2-carboxamidine: Using theprocedure described in Example 220, step (b), 22.0 mg (27.3% from methyl4-amino-5-methylthiothiophene-2-carboxylate) of4-(indan-5-ylamino)-5-methylthiothiophene-2-carboxamidine was obtained.¹H NMR (DMSO-d₆, 400 MHz) δ 1.94-2.01 (m, 2H), 2.49 (s, 3H), 2.77-2.82(m, 4H), 4.29 (d, 2H, J=5.6 Hz), 5.78 (t, 1H, J=8.1 Hz), 7.08 (d, 1H,J=7.8 Hz), 7.14 (d, 1H, J=7.5 Hz), 7.20 (s, 1H), 7.23 (s, 1H). Massspectrum (ESI, m/z): Calcd. for C₁₆H₁₉N₃S₂, 318.11 (M+H), found 318.3.

EXAMPLE 2224-(2,3-Dihydrobenzo[b]furan-5-ylamino)-5-methylthiothiophene-2-carboxamidine

a) Methyl4-(2,3-dihydrobenzo[b]furan-5-ylamino)-5-methylthiothiophene-2-carboxylate:Using the procedure described in Example 220, step (a), 60 mg (0.29mmol) of methyl 4-amino-5-methylthiothiophene-2-carboxylate, 42.9 mg(0.29 mmol) of 2,3-dihydrobenzo[b]furan-5-carboxaldehyde, and 135 mg(2.2 equiv, 0.63 mmol) of NaHB(OAc)₃ were allowed to react to givemethyl4-(2,3-dihydrobenzo[b]furan-5-ylamino)-5-methylthiothiophene-2-carboxylate.Mass spectrum (ESI, m/z): Calcd. for C₁₆H₁₇NO₃S₂, 336.07 (M+H), found334.3 (imine), 335.3.

b)4-(2,3-Dihydrobenzo[b]furan-5-ylamino)-5-methylthiothiophene-2-carboxamidine:Using the procedure described in Example 220, step (b), 21.8 mg (23.5%from methyl 4-amino-5-methylthiothiophene-2-carboxylate) of4-(2,3-dihydrobenzo[b]furan-5-ylamino)-5-methylthiothiophene-2-carboxamidinewas obtained. ¹H NMR (DMSO-d₆, 400 MHz) δ 2.49 (s, 3H), 3.13 (t, 2H,J=8.7 Hz), 4.24 (d, 2H, J=6.6 Hz), 4.48 (t, 2H, J=8.7 Hz), 5.69 (t, 1H,J=6.7 Hz), 6.68 (d, 1H, J=12.4 Hz), 7.06 (d, 1H, J=7.4 Hz), 7.21 (s,1H), 7.26 (s, 1H). Mass spectrum (ESI, m/z): Calcd. for C₁₅H₁₇N₃OS₂,320.09 (M+H), found 320.3.

EXAMPLE 2235-Methylthio-4-[(2-phenylimidazol-4-yl)amino]thiophene-2-carboxamidine

a) Methyl 5-methylthio-4-[(2-phenylimidazol-4-yl)amino]thiophene-2-carboxylate: Using the procedure described in Example220, step (a), 60 mg (0.29 mmol) of methyl4-amino-5-methylthiothiophene-2-carboxylate, 49.9 mg (0.29 mmol) of4-formyl-2-phenylimidazole, and 135 mg (2.2 equiv, 0.63 mmol) ofNaHB(OAc)₃ were allowed to react to give) methyl5-methylthio-4-[(2-phenylimidazol-4-yl)amino]thiophene-2-carboxylate.Mass spectrum (ESI, m/z): Calcd. for C₁₇H₁₇N₃O₂S₂, 360.08 (M+H), found360.0.

b)5-Methylthio-4-[(2-phenylimidazol-4-yl)amino]thiophene-2-carboxamidine:Using the procedure described in Example 220, step (b), 30.9 mg (30%from methyl 4-amino-5-methylthiothiophene-2-carboxylate) of5-methylthio-4-[(2-phenylimidazol-4-yl)amino]thiophene-2-carboxamidinewas obtained. ¹H NMR (DMSO-d₆, 400 MHz) δ 2.49 (s, 3H), 4.30-4.38 (m,3H), 7.09 (bs, 1H), 7.32 (m, 1H), 7.40-7.44 (m, 3H), 7.90-7.95 (m, 3H),8.43 (bs, 3H). Mass spectrum (ESI, m/z): Calcd. for C₁₆H₁₇N₅S₂, 344.10(M+H), found 344.2.

EXAMPLE 2245-Methylthio-4-[(2-quinolylmethyl)amino]thiophene-2-carboxamidine

a) Methyl5-methylthio-4-[(2-quinolylmethyl)amino]thiophene-2-carboxylate: Usingthe procedure described in Example 220, step (a), 60 mg (0.29 mmol) ofmethyl 4-amino-5-methylthiothiophene-2-carboxylate, 45.5 mg (0.29 mmol)of 2-quinolinecarboxaldehyde, and 135 mg (2.2 equiv, 0.63 mmol) ofNaHB(OAc)₃ were allowed to react to give methyl5-methylthio-4-[(2-quinolylmethyl)amino]thiophene-2-carboxylate. Massspectrum (ESI, m/z): Calcd. for C₁₇H₁₆N₂O₂S₂, 345.07 (M+H), found 343.3(imine), 345.2.

b) 5-Methylthio-4-[(2-quinolylmethyl)amino]thiophene-2-carboxamidine:Using the procedure described in Example 220, step (b), 2.5 mg (2.6%from methyl 4-amino-5-methylthiothiophene-2-carboxylate) of5-methylthio-4-[(2-quinolylmethyl)amino]thiophene-2-carboxamidine wasobtained. Mass spectrum (ESI, m/z): Calcd. for C₁₆H₁₆N₄S₂, 329.09 (M+H),found 329.3.

EXAMPLE 2254-({[(3-Hydroxyphenyl)methyl]amino}-5-methylthiothiophene-2-carboxamidine

a) Methyl4-{[(3-hydroxyphenyl)methylethyl]amino}-5-methylthiothiophene-2-carboxylate:Using the procedure described in Example 220, step (a), 61.6 mg (0.30mmol) of methyl 4-amino-5-methylthiothiophene-2-carboxylate, 49.5 mg(0.30 mmol) of 3-acetoxybenzaldehyde, and 135 mg (2.2 equiv, 0.63 mmol)of NaHB(OAc)₃ were allowed to react to give methyl4-{[(3-hydroxyphenyl)methyl]amino}-5-methylthiothiophene-2-carboxylate.Mass spectrum (ESI, m/z): Calcd. for C₁₄H₁₆NO₃S₂, 352.07 (M+H), found,350.2 (imine), 352.1.

b) Methyl4-{[(3-hydroxyphenyl)methyl]amino}-5-methylthiothiophene-2-carboxylate:Using the procedure described in Example 220, step (b), 7.9 mg (8.9%from methyl 4-amino-5-methylthiothiophene-2-carboxylate) of methyl4-{[(3-hydroxyphenyl) methyl]amino}-5-methylthiothiophene-2carboxylate;Mass spectrum (ESI, m/z): Calcd. for C₁₃H₁₅N₃OS₂, 294.07 (M+H), found294.3.

EXAMPLE 2265-Methylthio-4-(phenylcarbonylamino)thiophene-2-carboxamidine

a) Methyl 5-methylthio-4-(phenylcarbonylamino)thiophene-2-carboxylate:To a stirring solution of 114 mg (0.55 mmol) of methyl4-amino-5-methylthiothiophene-2-carboxylate in 4 mL of CH₂Cl₂ at 0° C.was added 142 μL (1.5 equiv, 0.82 mmol) of N,N-diisopropylethylamine viasyringe, followed by 71.3 μL (1.1 equiv, 0.61 mmol) of benzoyl chloride.The reaction was allowed to warm to room temperature, and stirred anadditional 4 h. At this time the reaction was partitioned in 40 mL of1:1 CH₂Cl₂-sat'd. NaHCO₃ (v/v) and the organic layer was separated,washed with 20 mL of brine, dried (Na₂SO₄), and concentrated in vacuo toafford 113 mg (66.8%) of methyl5-methylthio-4-(phenylcarbonylamino)thiophene-2-carboxylate which wasused without further purification. ¹H NMR (DMSO-d₆, 400 MHz) δ 2.55 (s,3H), 3.83 (s, 3H), 7.47-7.56 (m, 2H), 7.64 (m, 1H), 7.88 (s, 1H),7.93-7.99 (m, 2H), 10.12 (s, 1H). Mass spectrum (ESI, m/z): Calcd. forC14H₁₃NO₃S₂, 308.04 (M+H), found 308.2.

b) 5-Methylthio-4-(phenylcarbonylamino)thiophene-2-carboxamidine: Usinga procedure similar to Example 154, step (b), 100 mg (0.32 mmol) ofmethyl4-{[4-(methylethyl)phenyl]amino}-5-methylthiothiophene-2-carboxylate wasallowed to react with 8 equiv (2.58 mmol) of the AlMe₃NH₄Cl reagent toafford 95.4 mg (100%) of5-methylthio-4-(phenylcarbonylamino)thiophene-2-carboxamidine. ¹H NMR(DMSO-d₆, 400 MHz) δ 2.59 (s, 3H), 7.30-7.64 (m, 3H), 7.98-8.00 (m, 2H),8.23 (s, 1H), 9.19 (bs, 2H), 9.41 (bs, 2H), 10.35 (s, 1H). Mass spectrum(ESI, m/z): Calcd. for C₁₃H₁₄N₃OS₂, 292.06 (M+H), found 292.2.

EXAMPLE 227-240

To each of a series of 2-dram vials equipped a with a stir bar andTeflon septum was added between 0.3 and 0.6 mmol an acid chloride (1equiv), followed by 1 equiv of methyl4-amino-5-methylthiothiophene-2-carboxylate as a 1M CH₂Cl₂ solution. Anadditional 2 mL of CH₂Cl₂was charged into each vial, followed by 1.5equiv of N,N-diisopropylethylamine. Each vial was swept with Ar andallowed to stir for 3 h. At this time 4 mL of sat'd. NaHCO₃ was added toeach vial and stirring was continued for 5 min. The aqueous layers wereremoved by pipette and Na₂SO₄ was added to each vial. The vials wereallowed to stand overnight, and the contents then eluted through 5-gsilica gel (SPE column) cartridges with 0.5% MeOH—CH₂Cl₂. The amideswere concentrated in vacuo into pre-weighed 2-dram vials equipped with astir bar and Teflon septum for the subsequent amidination reactions. Thevials were purged with Ar and charged with 2 mL of toluene, followed by8 equiv of the AlMe₃/NH₄Cl reagent as a 1M solution in toluene. Thereactions were heated to 110° C. in a heating block for 3 h. They werethen cooled to ambient temperature and each was added by pipette to aslurry of 1.5 g silica gel in 15 mL of CH₂Cl₂. Each slurry wasvigorously stirred for 15 min, at which time they were filtered througha 15 mL sintered glass funnel containing 20 cm of silica gel with 50%CHCl₃-MeOH. The yellow fractions were collected and concentrated invacuo. The solids were triturated with 10% MeOH—CHCl₃ and filtered.Concentration in vacuo yielded the crude amidines, which were purifiedby preparative thin layer chromatography (20% MeOH—CHCl₃-sat'd. NH₃, 500μm SiO₂) to afford the amidines as their respective free bases.

Ex- am- % ple Acid Chloride Amidine Product Yield^(a) 227 cinnamoyl4-((2E)-3-phenylprop-2-enoylamino)- 15.3% chloride5-methylthiothiophene-2- carboxamidine 228 4-4-[(4-chlorophenyl)carbonylamino]-5- 44.6% chlorobenzoylmethylthiothiophene-2-carboxamidine chloride 229 cyclohexoyl4-(cyclohexylcarbonylamino)-5- 17.8% chloridemethylthiothiophene-2-carboxamidine 230 3-nitro-4- methyl4-[(4-methyl-3- 8.8% methylbenzoyl nitrophenyl)carbonylamino]-5-chloride methylthiothiophene-2-carboxylate 231 2-furoyl4-(2-furylcarbonylamino)-5- 13.3% chloridemethylthiothiophene-2-carboxamidine 232 2,2-dimethyl-4-(2,2-dimethylpropanoylamino)-5- 8.5% propanoylmethylthiothiophene-2-carboxamidine chloride 233 5-(3,5-4-{[5-(3,5-dichlorophenoxy)(2- 22.9% dichloro- furyl)]carbonylamino}-5-phenoxy)- methylthiothiophene-2-carboxamidine furan-2- carbonyl chloride234 1-napthoyl 5-methylthio-4- 3.1% chloride(naphthylcarbonylamino)-thiophene-2- carboxamidine 235 2-quinolinyl5-methylthio-4-(2-quinolylcarbonyl- 6.8% chlorideamino)thiophene-2-carboxamidine 236 3- 4-[(3-methoxyphenyl)carbonylamino]- 6.8% methoxy- 5-methylthiothiophene-2-benzoyl carboxamidine chloride 237 2-(2,5- 4-[2-(2-hydroxy-5- 18.3%dimethoxy- methoxyphenyl)acetylamino]-5- phenyl)methylthiothiophene-2-carboxamidine acetyl chloride 238 4-4-[(4-ethoxyphenyl)carbonytamino]-5- 34% ethoxybenzoylmethylthiothiophene-2-carboxamidine chloride 239 2- 5-methylthio-4-(2-10% phenoxyacetyl phenoxyacetylamino)-thiophene-2- chloridecarboxamidine 240 3- 4-[(3-methylphenyl)carbonylamino]-5- 21.1%methylbenzoyl methylthiothiophene-2-carboxamidine chloride ^(a)Yieldcalculated from starting methyl4-amino-5-methylthiothiophene-2-carboxylate.

EXAMPLE 2274-((2E)-3-Phenylprop-2-enoylamino)-5-methylthiothiophene-2-carboxamidine

a) Methyl4-((2E)-3-phenylprop-2-enoylamino)-5-methylthiothiophene-2-carboxylate:yield: 100%. ¹H NMR (DMSO-d₆, 400 MHz) δ 2.49 (s, 3H), 3.83 (s, 3H),7.12 (d, 1H, J=15.7 Hz), 7.41-7.66 (m, 6H), 8.24 (s, 1H), 9.92 (s, 1H).Mass spectrum (ESI, m/z): Calcd. for C₁₆H₁₅NO₃S₂, 334.06 (M+H), 334.1.

b)4-((2E)-3-Phenylprop-2-enoylamino)-5-methylthiothiophene-2-carboxamidine:¹H NMR (DMSO-d₆, 400 MHz) δ 2.54 (s, 3H), 7.13 (d, 1H, J=15.7 Hz),7.41-7.51 (m, 3H), 7.59-7.66 (m, 2H), 8.40 (s, 1H), 8.81 (bs, 3H), 10.02(bs, 1H). Mass spectrum (ESI, m/z): Calcd. for C₁₅H₁₅N₃OS₂, 318.07(M+H), 318.2.

EXAMPLE 2284-[(4-Chlorophenyl)carbonylamino]-5-methylthiothiophene-2-carboxamidine

a) Methyl4-[(4-chlorophenyl)carbonylamino]-5-methylthiothiophene-2-carboxylate:yield: 53%. ¹HNMR (DMSO-d₆, 400 MHz) δ 2.55 (s, 3H), 3.83 (s, 3H), 7.62(d, 2H, J=8.5 Hz), 7.87 (s, 1H), 7.97 (d, 2H, J=8.5 Hz), 10.21 (s, 1H).

b)4-[(4-Chlorophenyl)carbonylamino]-5-methylthiothiophene-2-carboxamidine:¹H NMR (DMSO-d₆ , 400 MHz) δ 2.59 (s, 3H) 7.63-7.66 (m, 2H), 7.98-8.01(m, 2H), 8.99 (bs, 2H), 9.33 (bs, 2H), 10.39 (s, 1H). Mass spectrum(ESI, m/z): Calcd. for C₁₃H₁₂ClN₃OS₂, 326.02 (M+H), found 326.2.

EXAMPLE 2294-(Cyclohexylcarbonylamino)-5-methylthiothiophene-2-carboxamidine

a) Methyl4-(cyclohexylcarbonylamino)-5-methylthiothiophene-2-carboxylate: yield:69.9%. ¹H NMR (DMSO-d₆, 400 MHz) δ 1.22-1.81 (m, 11H), 2.51 (s, 3H),3.82 (s, 3H), 7.97 (s, 1H), 9.55 (s, 1H). Mass spectrum (ESI, m/z):Calcd. for C₁₄H₁₉NO₃S₂, 314.09 (M+H), found 314.2.

b) 4-(Cyclohexylcarbonylamino)-5-methylthiothiophene-2-carboxamidine: ¹HNMR (DMSO-d₆, 400 MHz) δ 2.59 (s, 3H), 7.63-7.66 (m, 2H), 7.98-8.01 (m,2H), 8.99 (bs, 2H), 9.33 (bs, 2H), 10.39 (s, 1H). Mass spectrum (ESI,m/z): Calcd. for C₁₃H₂₀N₃OS₂, 298.10 (M+H), found 298.2.

EXAMPLE 230 Methyl4-[(4-methyl-3-nitrophenyl)carbonylamino]-5-methlylthiothiophene-2-carboxylate

a) Methyl4-[(4-methyl-3-nitrophenyl)carbonylamino]-5-methylthiothiophene-2-carboxylate:yield: 80%. ¹H NMR (DMSO-d₆, 400 MHz) δ 2.56 (s, 3H), 2.61 (s, 3H), 3.82(s, 3H), 7.70 (d, 1H, J=8.1 Hz), 7.86 (s, 1H), 8.19 (dd, 1H, J=1.7, 8.0Hz), 8.56 (d, 1H, J=1.7 Hz), 10.41 (s, 1H). Mass spectrum (ESI, m/z):Calcd. for C₁₅H₁₄N₂O₅S₂, 367.42 (M+H), found 367.2.

b) Methyl4-[(4-methyl-3-nitrophenyl)carbonylamino]-5-methylthiothiophene-2-carboxylate:¹H NMR (DMSO-d₆, 400 MHz) δ 2.47 (s, 3H), 2.61 (s, 3H), 7.12 (bs, 3H),7.69-7.73 (m, 2H), 8.20 (dd, 1H. J=1.6, 7.9 Hz), 8.57 (d, 1H, J=1.6 Hz).Mass spectrum (ESI, m/z): Calcd. for C₁₄H₁₄N₄O₃S₂, 351.06 (M+H), found351.2.

EXAMPLE 2314-(2-Furylcarbonylamino)-5-methylthiothiophene-2-carboxamidine

a) Methyl 4-(2-Furylcarbonylamino)-5-methylthiothiophene-2-carboxylate:yield: 100%; ¹H NMR (DMSO-d₆, 400 MHz) δ 2.54 (s. 3H), 3.83 (s, 3H),6.71 (dd, 1H, J=1.8, 3.4 Hz), 7.33 (d, 1H, J=3.5 Hz), 7.87 (s, 1H), 7.95(m, 1H), 9.93 (s, 1H). Mass spectrum (ESI, m/z): Calcd. for C₁₂H₁₁NO₄S₂,298.02 (M+H), found 298.3.

b) 4-(2-Furylcarbonylamino)-5-methylthiothiophene-2-carboxamidine: ¹HNMR (DMSO-d₆, 400 MHz) δ 2.51 (s, 3H, 6.71 (dd, 1H, J=1.8, 3.5 Hz), 7.18(bs, 3H), 7.32 (d, 1H, J=3.4 Hz), 7.79 (s, 1H), 7.96 (m, 1H). Massspectrum (ESI, m/z): Calcd. for C₁₁H₁₁N₃O₂S₂, 282.04 (M+H), found 282.2.

EXAMPLE 2324-(2,2-Dimethylpropanoylamino)-5-methylthiothiophene-2-carboxamidine

a) Methyl4-(2,2-dimethylpropanoylamino)-5-methylthiothiophene-2-carboxylate:yield: 93.4%. ¹H NMR (DMSO-d₆, 400 MHz) δ 1.23 (s, 9H), 2.51 (s, 3H),3.81 (s, 3H), 7.74 (s, 1H), 9.04 (s, 1H). Mass spectrum (ESI, m/z):Calcd. for C₁₂H₁₇NO₃S₂, 288.07 (M+H), found 288.1.

b) 4-(2,2-Dimethylpropanoylamino)-5-methylthiothiophene-2-carboxamidine:¹H NMR (DMSO-d₆, 400 MHz) δ 1.24 (s, 9H), 2.55 (s, 3H), 8.05 (s, 1H),9.0 (bs, 3H), 9.1 (s, 1H). Mass spectrum (ESI, m/z): Calcd. forC₁₁H₁₇N₃OS₂, 272.09 (M+H), found 272.2.

EXAMPLE 2334-{[5-(3,5-Dichlorophenoxy)(2-furyl)]carbonylamino}-5-methylthiothiophene-2-carboxamidine

a) Methyl4-{[5-(3,5-dichlorophenoxy)(2-furyl)]carbonylamino}-5-methylthiothiophene-2-carboxylate:yield: 96.9%. Mass spectrum (ESI, m/z): Calcd. for C₁₈H₁₃C₁₂NO₅S₂,457.97 (M+H), found 457.9.

b)4-{[5-(3,5-Dichlorophenoxy)(2-furyl)]carbonylamino}-5-methylthiothiophene-2-carboxamidine:¹H NMR (DMSO-d₆, 400 MHz) δ 2.53 (s, 3H), 6.12-6.17 (m, 1H), 6.79 (d,1H, J=1.8 Hz), 7.40-7.43 (m, 2H), 7.70 (m, 1H), 8.13 (s, 1H), 8.92 (bs,2H), 9.21 (bs, 1H). 10.06 (s, 1H). Mass spectrum (ESI, m/z): Calcd. forC₁₇H₁₄C₁₂N₃O₃S₂, 441.99 (M+H), found 442.2.

EXAMPLE 2345-Methylthio-4-(naphthylcarbonylamino)thiophene-2-carboxamidine

a) Methyl 5-methylthio-4-(naphthylcarbonylamino)thiophene-2-carboxylate:yield: 80.8%. ¹H NMR (DMSO-d₆, 400 MHz) δ 7.59-7.67 (m, 3H), 7.80 (d,1H, J=6.8 Hz), 8.02-8.34 (m, 4H), 10.38 (s, 1H).

b) 5-Methylthio-4-(naphthylcarbonylamino)thiophene-2-carboxamidine: ¹HNMR (DMSO-d₆, 400 MHz) δ 2.50 (s, 3H), 7.60 (m, 3H), 7.76 (d, 1H, J=6.7Hz), 7.94 (s, 1H), 8.03 (d, 1H, J=6.8 Hz), 8.09 (d, 1H, 8.3 Hz), 8.30(d, 1H, J=8.8 Hz). Mass spectrum (ESI, m/z): Calcd. for C₁₇H₁₅N₃OS₂,342.07 (M+H), found 342.2.

EXAMPLE 2355-Methylthio-4-(2-quinolylcarbonylamino)thiophene-2-carboxamidine

a) Methyl5-methylthio-4-(2-quinolylcarbonylamino)thiophene-2-carboxylate: yield:80.9%. ¹H NMR (DMSO-d₆, 400 MHz) δ 2.59 (s, 3H), 3.86 (s, 3H), 8.03-8.06(m, 3H), 8.24-8.29 (m, 3H), 9.58 (s, 1H), 10.63 (s, 1H).

b) 5-Methylthio-4-(2-quinolylcarbonylamino)thiophene-2-carboxamidine: ¹HNMR (DMSO-d₆, 400 MHz) δ 2.53 (s, 3H), 7.21 (bs, 3H), 7.74 (s, 1H),7.96-7.98 (m, 2H), 8.19-8.22 (m, 4H), 9.77 (s, 1H). Mass spectrum (ESI,m/z): Calcd. for C₁₆H₁₄N₄OS₂, 343.45 (M+H), found 343.1.

EXAMPLE 2364-[(3-Methylphenyl)carbonylamino]-5-methylthiothiophene-2-carboxamidine

a) Methyl4-[(3-methylphenyl)carbonylamino]-5-methlylthiothiophene-2-carboxylate:yield: 90.3%. ¹H NMR (DMSO-d₆, 400 MHz) δ 2.55 (s, 3H), 3.83 (s, 3H),3.85 (s, 3H), 7.19 (m, 1H), 7.39-7.59 (m, 3H), 7.85 (s, 1H), 10.09 (s,1H). Mass spectrum (ESI, m/z): Calcd. for C₁₅H₁₅NO₄S₂, 338.05 (M+H),found 338.3.

b)4-[(3-Methoxyphenyl)carbonylamino]-5-methylthiothiophene-2-carboxamidine:¹H NMR (DMSO-d₆, 400 MHz) δ 2.58 (s, 3H), 3.84 (s, 3H), 7.19 (dd, 1H,J=2.1, 8.1 Hz), 7.45-7.57 (m, 3H), 8.15 (s, 1H), 9.11 (bs, 4H), 10.32(bs, 1H). Mass spectrum (ESI, m/z): Calcd. for C₁₄H₁₅N₃O₂S₂, 322.07(M+H), found 322.2.

EXAMPLE 2374-[2,5-Dimethoxyphenyl)acetylamino]-5-methylthiothiophene-2-carboxamidine

a) Methyl4-[2-(2,5-dimethoxyphenyl)acetylamino]-5-methlylthiothiophene-2-carboxylate:¹H NMR (DMSO-d₆, 400 MHz) δ 2.47 (s, 3H), 3.67 (s, 2H), 3.70 (s, 3H),3.75 (s, 3H), 3.80 (s, 3H), 6.81 (dd, 1H, J=3.0, 8.8 Hz), 6.87 (d, 1H,J=3.0 Hz), 6.93 (d, 1H, J=8.9 Hz), 8.04 (s, 1H), 9.62 (s, 1H);

b)4-[2-(2,5-Dimethoxyphenyl)acetylamino]-5-methylthiothiophene-2-carboxamidine:¹H NMR (DMSO-d₆, 400 MHz) δ 2.38 (s, 3H), 3.66 (s, 2H), 3.70 (s, 3H),3.76 (s, 3H), 6.81 (dd, 1H, J=3.3, 8.0 Hz), 6.88-6.94 (m, 2H), 7.91 (s,1H), 9.42 (bs, 1H).

EXAMPLE 2384-[(4-Ethoxyphenyl)carbonylamino]-5-methylthiothiophene2-carboxamidine

a) Methyl4-[(4-ethoxyphenyl)carbonylamino-5-methylthiothiophene-2-carboxylate: ¹HNMR (DMSO-d₆, 400 MHz) δ 1.36 (t, 3H, J=7.0 Hz), 2.54 (s, 3H), 3.83 (s,3H), 4.13 (q, 2H, J=7.0 Hz), 7.05 (d, 2H, J=8.8 Hz), 7.87 (s, 1H), 7.93(d, 2H, J=8.8 Hz), 9.93 (s, 1H). Mass spectrum (ESI, m/z): Calcd. forC₁₆H₁₇NO₄S₂, 352.07 (M+H), found 352.2.

b)4-[(4-Ethoxyphenyl)carbonylamino]-5-methylthiothiophene-2-carboxamidine:¹H NMR (DMSO-d₆, 400 MHz) δ 1.36 (t, 3H, J=7.0 Hz). 2.55 (s, 3H), 4.13(q, 2H, J=7.0 Hz), 7.04-7.08 (m, 2H), 7.94-7.97 (m, 2H), 8.09 (s,1H);8.73 (bs, 3H), 10.01 (bs, 1H). Mass spectrum (ESI. m/z): Calcd. forC₁₅H₁₇N₃O₂S₂, 336.08 (M+H), found 336.2.

EXAMPLE 2395-Methylthio-4-(2-phenoxyacetylamino)thiophene-2-carboxamidine

a) Methyl 5-methylthio-4-(2-phenoxyacetylamino)thiophene-2-carboxylate:yield: 79%. ¹H NMR (DMSO-d₆, 400 MHz) δ 2.48 (s, 3H), 3.82 (s, 3H), 4.78(s, 2H), 6.97-7.02 (m, 2H), 7.31-7.35 (m, 2H), 8.05 (s. 1H), 9.80 (s,1H).

b) 5-Methylthio-4-(2-phenoxyacetylamino)thiophene-2-carboxamidine: ¹HNMR (DMSO-d₆, 400 MHz): δ 2.52 (s, 3H). 4.81 (s, 2H), 6.97-7.04 (m, 3H),7.31-7.35 (m, 2H), 8.26 (s, 1H), 8.84 (bs, 4H). Mass spectrum (ESI,m/z): Calcd. for C₁₄H₁₅N₃O₂S₂, 322.43 (M+H), found 322.2.

EXAMPLE 2404-[(3-Methylphenyl)carbonylamino]-5-methylthiothiophene-2-carboxamidine

a) Methyl4-[(3-methylphenyl)carbonylamino]-5-methylthiothiophene-2-carboxylate:yield: 79%. ¹H NMR (DMSO-d₆, 400 MHz) δ 2.40 (s, 3H), 2.55 (s, 3H), 3.83(s, 3H), 4.78 (s, 2H), 7.42-7.43 (m, 2H), 7.47-7.77 (m, 2H), 7.86 (s,1H), 10.06 (s, 1H). Mass spectrum (ESI, m/z): Calcd. for C₁₅H₁₅NO₃S₂,322.06 (M+H), found 322.2.

b)4-[(3-Methylphenyl)carbonylamino]-5-methylthiothiophene-2-carboxamidine:¹H NMR (DMSO-d₆, 400 MHz) 2 2.40 (s, 3H), 2.55 (s, 3H), 7.43-7.44 (m,2H), 7.75-7.78 (m, 2H), 8.05 (s, 1H), 8.52 (bs, 3H), 10.12 (bs, 1H).Mass spectrum (ESI, m/z): Calcd. for C₁₄H₁₅N₃OS₂, 306.07 (M+H), found306.2.

EXAMPLE 241

a) Methyl 4-bromo-5-methylthiothiophene-2-carboxylate: To a stirredsolution of 4-bromo-5-methylthiothiophene-2-carboxylic acid (87 mmol),prepared according to the procedure of Kleemann, et al., EP 0676395A2,in dry methanol (750 mL) was added thionyl chloride (7 mL, 96 mmol)dropwise. After stirring for 10 min at room temperature, the solutionwas heated to reflux and stirred 7.5 h. The solution was cooled and thesolvents were removed in vacuo. The resulting solid was dissolved indichloromethane (1500 mL) and washed with saturated sodium bicarbonate(2×300 mL), water (300 mL), saturated brine (300 mL), and dried overanhydrous sodium sulfate. The solvents were removed in vacuo. Theresulting solid was recrystallized twice from hexane/ethyl acetate togive methyl 4-bromo-5-methylthiothiophene-2-carboxylate (4.4 g, 19%).¹H-NMR (CDCl₃, 400 MHz) δ 7.66 (s, 1H), 3.90 (s, 3H), 2.60 (s, 3H).

b) Methyl5-methylthio-4-{[3-(phenylmethoxy)phenyl]amino}thiophene-2-carboxylate:A dry mixture of 60 mg (0.225 mmol) of methyl4-bromo-5-methylthiothiophene-2-carboxylic acid, as prepared in theprevious step, 3.0 mg (6 mole %) of palladium (II) acetate (AldrichChemical Co., Milwaukee, Wis.), 12.6 mg (9 mole %) ofracemic-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (Strem, Newburyport,Mass.), 110 mg (0.34 mmol, 1.5 eq) of cesium carbonate (Aldrich ChemicalCo., Milwaukee, Wis.), and 54 mg (0.29 mmol, 1.3 eq) of3-benzyloxyaniline (Aldrich Chemical Co., Milwaukee, Wis.) was added toan oven-dried 1-dram glass vial. This vial was flushed with dry argon ina glove bag, dry toluene (450 μL, 0.5 M) was added, and the assembly washeated at 100° C. for 36 h. To the cooled suspension ethyl acetate (4mL) was added, the mixture passed through 1 inch of Celite, washed withethyl acetate (2×4 mL) and the solvents removed in vacuo. Purificationby preparative thin-layer chromatography (1:1 dichloromethane/hexanes)gave 13 mg of the title compound (15%) as a pale yellow solid. ¹H-NMR(CDCl₃, 400 MHz) δ 7.77 (s, 1H), 7.47-6.59 (m, 9H), 6.11 (s, 1H), 5.07(s, 2H), 3.89 (s, 3H), 2.47 (s, 3H). Mass spectrum (ESI, m/z): Calcd.for C₂₀H₁₉NO₃S₂, 386.1 (M+H), found 386.3.

c)5-Methylthio-4-{[3-(phenylmethoxy)phenyl]amino}thiophene-2-carboxamidine:Trimethylaluminum (2.0 M in toluene, 2 mL) was added dropwise over 10min to a suspension of ammonium chloride (216 mg) in toluene (2 mL),stirred under dry nitrogen at 0° C. After the mixture was stirred at 25°C. for 30 min, when most of the solid had dissolved, this mixture wastaken up in a syringe and added to 13 mg (0.03 mmol) of methyl5-methylthio-4-{[3-(phenylmethoxy)phenyl]amino}thiophene-2-carboxylate.The reaction mixture was heated to reflux in stages and stirred for 2h10 min. The cooled mixture was poured in to a vigorously stirred slurryof silica gel (2 g) in chloroform (20 mL). To this suspension methanol(50 mL) was added, the mixture was passed through 1 inch of silica gelin a sintered glass Büchner funnel, washed with methanol (50 mL), andthe solvents removed in vacuo. The crude product was purified on a 5 gsilica gel SPE column washing first with dichloromethane and theneluting the product off with 10% methanol in dichloromethane. Theproduct was further purified by preparative High Pressure LiquidChromatography (HPLC) on a Dynamax C18 column, 60 Å pore size, 10 μMparticle size, 40 to 100% methanol over 30 min in 0.1% trifluoroaceticacid to give 5.4 mg of the title compound (45%) as a yellow solid.¹H-NMR (CD₃OD, 400 MHz) δ 7.84 (s, 1H), 7.44-6.60 (m, 9H), 5.08 (s, 2H),2.48 (s, 3H). Mass spectrum (ESI, m/z): Calcd. for C₁₉H₁₉N₃OS₂, 370.1(M+H), found 370.2.

EXAMPLE 242

a) Methyl5-methylthio-4-[(3-phenoxyphenyl)amino]thiophene-2-carboxylate: Astirred suspension of 80 mg (0.299 mmol) of methyl4-bromo-5-methylthiothiophene-2-carboxylate and 72 mg (0.389 mmol, 1.3eq) of 3-phenoxyaniline (Aldrich, Milwaukee, Wis.) was treated as inExample 241, step (b). Further purification of the product bypreparative thin layer chromatography eluting with 10% ethyl acetate inhexane gave 36 mg of the title compound (32%) as a yellow oil. ¹H-NMR(CDCl₃, 400 MHz) δ 7.76 (s, 1H), 7.40-6.65 (m, 9H), 6.26 (s, 1H); 3.89(s, 3H), 2.40 (s, 3H). Mass spectrum (ESI, m/z): Calcd. for C₁₉H₁₇NO₃S₂,372.1 (M+H), found 372.2.

b) 5-Methylthio-4-[(3-phenoxyphenyl)amino]thiophene-2-carboxamidine:Methyl 5-methylthio-4-[(3-phenoxyphenyl)amino]thiophene-2-carboxylate(36 mg, 0.097 mmol) was treated as in Example 241, step (c), but withoutHPLC purification to give 30 mg of the title compound (86%) as an orangeglass. ¹H-NMR (CDCl₃, 400 MHz) δ 9.28 (s, 2H), 8.11 (s, 2H), 7.99 (s,1H), 7.34-6.50 (m, 9H), 6.29 (s, 1H), 2.35 (s, 3H). Mass spectrum (ESI,m/z): Calcd. for C₁₈H₁₇N₃OS₂, 356.1 (M+H), found 356.2.

EXAMPLE 243

a) 5-Methylthio-4-[(4-phenoxyphenyl)amino]thiophene 2-carboxamidine: Astirred suspension of 80 mg (0.299 mmol) of methyl4-bromo-5-methylthiothiophene-2-carboxylate and 72 mg (0.389 mmol, 1.3eq)of 4-phenoxyaniline (Aldrich, Milwaukee, Wis.) was treated as inExample 241, step (b). Further purification of the product bypreparative thin layer chromatography eluting with 10% ethyl acetate inhexane gave 53 mg of the title compound (48%) as a yellow oil. ¹H-NMR(CDCl₃, 400 MHz) δ 7.70 (s, 1H), 7.34-7.00 (m, 9H), 6.11 (s, 1H), 3.89(s, 3H), 2.42 (s, 3H). Mass spectrum (ESI, m/z): Calcd. for C19H₁₇NO₃S₂,372.1 (M+H), found 372.1.

b) 5-Methylthio-4-[(4-phenoxyphenyl)amino]thiophene-2-carboxamidine:Methyl 5-methylthio-4-[(4-phenoxyphenyl)amino]thiophene-2-carboxylate(53 mg, 0.14 mmol) was treated as in Example 241, step (c), but withoutHPLC purification to give 58 mg of the title compound (quantitativeyield) as an orange glass. ¹H-NMR (CDCl₃, 400 MHz) δ 8.89 (s 2H), 8.00(s, 1H), 7.25-6.87 (m, 9H), 6.20 (s, 1H), 2.27 (s, 3H). Mass spectrum(ESI, m/z): Calcd. for C₁₈H₁₇N₃OS₂, 356.1 (M+H), found 356.2.

EXAMPLE 244

a) Methyl4-[(2-methoxyphenyl)amino]-5-methylthiothiophene-2-carboxylate: Astirred suspension of 103 mg (0.386 mmol) of methyl4-bromo-5-methylthiothiophene-2-carboxylate and 57 mg (0.46 mmol, 1.2eq)of 2-methoxyaniline (Aldrich, Milwaukee, Wis.) was treated in amanner similar to Example 241, step (b) to give 78 mg the title compound(65%) as a yellow oil. ¹H-NMR (CDCl₃, 400 MHz) δ 7.82 (s, 1H), 7.12-6.52(m, 4H), 6.52 (s, 1H), 3.92 (s, 3H), 3.87 (s, 3H), 2.40 (s, 3H). Massspectrum (ESI, m/z): Calcd. for C₁₄H₁₅NO₃S₂, 310.1 (M+H), found 310.2.

b) 4-[(2-Methoxyphenyl)amino]-5-methylthiothiophene-2-carboxamidine:Methyl 4-[(2-methoxyphenyl)amino]-5-methylthiothiophene-2-carboxylate(78 mg, 0.25 mmol) was treated as in Example 241, step (c), but withoutHPLC purification to give 75 mg of the title compound (quantitativeyield) as an orange glass. ¹H-NMR (CD₃OD, 400 MHz) δ 7.91 (s, 1H),7.15-6.93 (m, 4H), 3.93 (s, 3H), 2.48 (s, 3H). Mass spectrum (ESI, m/z):Calcd. for C₁₃H₁₅N₃OS₂, 294.1 (M+H), found 294.2.

EXAMPLE 245

a) Methyl 4-[(2-methylphenyl)amino]-5-methylthiothiophene-2-carboxylate:A dry mixture of 100 mg (0.374 mmol) of methyl4-bromo-5-methylthiothiophene-2-carboxylate, 51 mg (14.9 mole %) oftris(dibenzylideneacetone)dipalladium (Lancaster, Pelham, N.H.), 52 mg(22.3 mole %) of racemic-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl(Strem, Newburyport, Mass.), 183 mg of (0.56 mmol, 1.5 eq) cesiumcarbonate (Aldrich Chemical Co., Milwaukee, Wis.), and 71 μL (0.49 mmol,1.3 eq) of 2-methylaniline (Aldrich Chemical Co., Milwaukee, Wis.) wasadded to an oven-dried 1-dram glass vial. This vial was flushed with dryargon in a glove bag, dry toluene (750 μL, 0.5 M) was added, and theassembly was heated at 100° C. for 40 h. To the cooled suspension ethylacetate (4 mL) was added, the mixture passed through 1 inch of Celite,washed with ethyl acetate (2×4 mL) and the solvents removed in vacuo.Purification by preparative thin-layer chromatography (1:1dichloromethane/hexanes) gave 67 mg of the title compound (61%) as ayellow oil. ¹H-NMR (CDCl₃, 400 MHz) δ 7.64 (s, 1H), 7.23-6.94 (m, 4H),5.91 (br s, 1H), 3.88 (s, 3H), 2.41 (s, 3H), 2.31 (s, 3H). Mass spectrum(ESI, m/z): Calcd. for C₁₄H₁₅NO₂S₂, 294.1 (M+H), found 294.2.

b) 4-[(2-Methylphenyl)amino]-5-methylthiothiophene-2-carboxamidine:Methyl 4-[(2-methylphenyl)amino]-5-methylthiothiophene-2-carboxylate (67mg, 0.23 mmol) was treated as in Example 241, step (c), but without HPLCpurification to give 20 mg of the title compound (30%) as a yellowglass. ¹H-NMR (CD₃0D; 400 MHz) δ 7.56 (s, 1H), 7.24-6.99 (m, 4H), 2.49(s, 3H), 2.29 (s, 3H). Mass spectrum (ESI, m/z): Calcd. for C₁₃H₁₅N₃S₂,278.1 (M+H), found 278.2.

EXAMPLE 246

a) Methyl 4-[(3-chlorophenyl)amino]-5-methylthiothiophene-2-carboxylate:A stirred suspension of 80 mg (0.299 mmol) of methyl4-bromo-5-methylthiothiophene-2-carboxylate and 41 μL (0.389 mmol, 1.3eq) of 3-chloroaniline (Aldrich, Milwaukee, Wis.) was treated in amanner similar to Example 241, step (b) to give 47 mg of the titlecompound (50%) as a yellow oil. ¹H-NMR (CDCl₃, 400 MHz) δ 7.75 (s, 1H),7.23-6.89 (m. 4H), 6.10 (s, 1H), 3.89 (s, 3H), 2.42 (s, 3H). Massspectrum (ESI, m/z): Calcd. for C₁₃H₁₂NO₂S₂Cl, 314.0 (M+H), found 314.1.

b) 4-[(3-Chlorophenyl)amino]-5-methylthiothiophene-2-carboxamidine:Methyl 4-[(3-chlorophenyl)amino]-5-methylthiothiophene-2-carboxylate (47mg, 0.15 mmol) was treated as in Example 241, step (c) to give 33 mg ofthe title compound (75%) as a light yellow solid. ¹H-NMR(DMSO-d₆, 400MHz) δ 9.22 (s, 2H), 8.81 (s, 2H), 8.22 (s, 1H), 7.99 (s, 1H), 7.24-6.82(m, 4H), 2.53 (s, 3H). Mass spectrum (ESI, m/z): Calcd. forC₁₂H₁₂N₃S₂Cl, 298.0 (M+H), found 298.3.

EXAMPLE 247

a) Methyl 4-(methylphenylamino)-5-methylthiothiophene-2-carboxylate: Astirred suspension of 100 mg (0.374 mmol) of methyl4-bromo-5-methylthiothiophene-2-carboxylate and 72 μL (0.487 mmol, 1.3eq) of N-methylaniline (Aldrich Chemical Co., Milwaukee, Wis.) wastreated in a manner similar to Example 245, step (a) to give 23 mg ofthe title compound (21%) as a yellow oil. ¹H-NMR (CDCl₃, 400 MHz) δ 7.61(s, 1H), 7.26-6.68 (m, 5H), 3.89 (s, 3H), 3.25 (s, 3H), 2.50 (s, 3H).Mass spectrum (ESI, m/z): Calcd. for C₁₄H₁₅NO₂S₂, 294.1 (M+H), found294.3.

b) 4-(Methylphenylamino)-5-methylthiothiophene-2-carboxamidine: Methyl4-[(2-methylphenyl)amino]-5-methylthiothiophene-2-carboxylate (23 mg,0.078 mmol) was treated as in Example 241, step (c), but without HPLCpurification to give 5.6 mg of the title compound (26%) as a yellowglass. ¹H-NMR (CD₃OD, 400 MHz) δ 7.83 (s, 1H), 7.24-6.71 (m, 4H), 3.27(s, 3H), 2.57 (s, 3H). Mass spectrum (ESI, m/z): Calcd. for C₁₃H₁₅N₃S₂,278.1 (M+H), found 278.3.

EXAMPLE 248

a) Methyl 5-methyl-4-(phenylamino)thiophene-2-carboxylate: A stirredsuspension of 400 mg (1.7 mmol) methyl5-methyl-4-bromo-thiophene-2-carboxylate and 192 μL (2.1 mmol, 1.25 eq)of aniline (Aldrich, Milwaukee, Wis.) was treated in a manner similar toExample 241, step (b) to give 66 mg of the title compound (16%) as abrown glass. ¹H-NMR (DMSO-d₆, 400 MHz) δ 7.70 (s, 1H), 7.56 (s, 1H),7.17 (m, 2H), 6.72 (m, 3H), 3.79 (s, 3H), 2.31 (s, 3H). Mass spectrum(MALDI, gentisic acid matrix, mn/z): Calcd. for C₁₃H₁₃NO₂S, 248.1 (M+H),found 247.5.

b) 5-Methyl-4-(phenylamino)thiophene-2-carboxamidine: Methyl4-(methylphenylamino)-5-methylthiothiophene-2-carboxylate (66 mg, 0.27mmol) was treated as in Example 241, step (c), but without HPLCpurification to give 57 mg of the title compound (91%) as a brown glass.¹H-NMR (DMSO-d₆, 400 MHz) δ 9.17 (s, 2H), 8.85 (s, 2H), 7.98 (s, 1H),7.85 (s, 1H), 7.21-6.73 (m, 5H), 2.39 (s, 3H). Mass spectrum (ESI, m/z):Calcd. for C₁₂H₁₃N₃S, 232.1 (M+H), found 232.2.

EXAMPLE 249

a) Methyl4-{[4-(dimethylamino)phenyl]amino}-5-methylthiothiophene-2-carboxylate:A stirred suspension of 100 mg (0.267 mmol) methyl5-methyl-4-bromo-thiophene-2-carboxylate and 66 mg (0.35 mmol, 1.3 eq)of 4-amino-N,N-dimethylaniline (Fluka, Milwaukee, Wis.) was treated in amanner similar to Example 241, step (b), but eluting with 1:1 ethylacetate/hexane for preparative thin-layer chromatrography purification,to give 86 mg of the title compound (quantitative yield) as an orangeglass. ¹H-NMR (CDCl₃, 400 MHz) δ 7.53 (s, 1H), 7.16 and 6.62 (ABquartet, 4H, J=8.9 Hz), 5.99 (s, 1H), 3.86 (s, 3H), 2.94 (s, 6H), 2.39(s, 3H). Mass spectrum (ESI, m/z): Calcd. for C₁₅H₁₈N₂O₂S₂, 323.1 (M+H),found 323.3.

b)4-{[4-(Dimethylamino)phenyl]amino)-5-methylthiothiophene-2-carboxamidine:Methyl 4-(methylphenylamino)-5-methylthiothiophene-2-carboxylate (86 mg,0.267 mmol) was treated as in Example 241, step (c), but without HPLCpurification. This material was further purified by passing through 1inch of basic alumina and eluting with 10% methanol in dichloromethane(15 mL) to give 62 mg of the title compound (76%) as a brown glass.¹H-NMR (DMSO-d₆, 400 MHz) δ 8.95 (s. 4H), 7.75 (s, 1H), 7.56 (s, 1H),6.97 and 6.72 (AB quartet, 4H, J=8.9 Hz). 2.83 (s, 6H), 2.44 (s, 3H).Mass spectrum (ESI, m/z): Calcd. for C₁₄H₁₈N₄S₂, 307.1 (M+H), found307.3.

EXAMPLE 2504-[(4-Ethylphenyl)amino]-5-methylthiothiophene-2-carboxamidinehydrochloride

a) Methyl 4-[(4-etylphenyl)amino]-5-methylthiothiophene-2-carboxylate:To an oven-dried glass vial with stir bar was added a mixture of 100 mg(0.374 mmol) of methyl 4-bromo-5-methylthiothiophene-2-carboxylate (asprepared in Example 241, step (a)), 5.8 mg (6.9 mmol %) of palladium(II) acetate, 21.7 mg (9.3 mmol %) ofracemic-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl , 171.5 mg (0.526mmol) of cesium carbonate and 59 mg (0.487 mmol) of 4-ethylaniline. Thevial was transferred to a glove bag, flushed with dry argon andanhydrous toluene (749 μL) was added. The vial was capped with aTeflon-lined screw cap and heated at 100° C. for 48 h. The cooledsuspension was filtered (Celite) washing with ethyl acetate (2×2 mL),and the solvents removed in vacuo. The resulting residue was purified on1 mm silica prep plates eluting with 40% methylene chloride-hexanes toafford 14 mg (12%) of methyl4-[(4-ethylphenyl)amino]-5-methylthiothiophene-2-carboxylate as a paleyellow resin which was used directly in the following step.

b) 4-[(4-Ethylphenyl)amino]-5-methylthiothiophene-2-carboxamidinehydrochloride: Trimethylaluminum (2.0 M in toluene, 0.182mL, 0.363 mmol)was added dropwise to a suspension of ammonium chloride (19 mg, 0.363mmol) in anhydrous toluene (1 mL) under Ar at 0° C. The mixture wasstirred at 25° C. for 30 min and then 14 mg (0.036 mmol) of methyl4-[(4-ethylphenyl)amino]-5-methylthiothiophene-2-carboxylate (asprepared in previous step) was added. The reaction mixture was heatedslowly to 100° C. and stirred for 4 h. The cooled mixture was added to avigorously stirred slurry of silica gel (1.3 g) in chloroform (20 mL).The suspension was filtered (silica) washing with 50% MeOH—CH₂Cl₂ (2×50mL). The washings were concentrated and the resulting residue waspurified on a 0.5 mm silica prep plate eluting with a 10% MeOH—CH₂Cl₂ toafford 8 mg (67%) of4-[(4-ethylphenyl)amino]-5-methylthiothiophene-2-carboxamidinehydrochloride as a yellow oil. ¹H-NMR (CD₃OD, 400 MHz) δ 87.84 (s, 1H),7.14 (d 2H, 8 Hz), 7.01 (d, 2H, 8 Hz), 2.55 (q, 2H, 65.5 Hz), 2.48 (s,3H), 1.23 (t, 3H, 15.2 Hz). Mass spectrum (ESI, m/z): Calcd. forC₁₄H₁₇N₃S₂, 292.1 (M+H), found 292.5.

EXAMPLE 2515-Methylthio-4-{[4-(phenylmethoxy)phenyl]amino}thiophene-2-carboxamidinehydrochloride

a) Methyl5-methylthio-4-{[4-(phenylmethoxy)phenyl]amino}thiophene-2-carboxylate:The same procedure as in Example 250, step a was followed using 100 mg(0.374 mmol) of methyl 4-bromo-5-methylthiothiophene-2-carboxylate (asprepared in Example 241, step (a)), 5.5 mg (6.5 mmol %) of palladium(II) acetate, 23.6 mg (10.1 mmol %) ofracemic-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl, 194 mg (0.595 mmol)of cesium carbonate, 97.3 mg (0.488 mmol) of 4-benzyloxyaniline and 749μL of toluene, and chromatographed as before using 40% CH₂Cl₂-hexane toafford 7 mg (5%) of methyl5-methylthio-4-{[4-(phenylmethoxy)phenyl]amino)}thiophene-2-carboxylateas a yellow resin which was used directly in the following step.

b)5-Methylthio-4-{[4-(phenylmethoxy)phenyl]amino}thiophene-2-carboxamidinehydrochloride: The same procedure as in Example 250, step (b) wasfollowed using 7 mg (0.018 mmol) of methyl5-methylthio-4-{[4-phenylmethoxy)phenyl]amino }thiophene-2-carboxylate(as prepared in previous step), 0.091 mL of trimethylaluminum (2.0 M intoluene, 0.182 mmol), 10 mg of ammonium chloride (0.182 mmol) and 1 mLof toluene, and purified on a 0.5 mm silica prep plate eluting with 10%MeOH—CH₂Cl₂ to afford 3 mg (41%) of5-methylthio-4-{[⁴-(phenylmethoxy)phenyl]amino}thiophene-2-carboxamidinehydrochloride as a yellow oil. ¹H-NMR (CD₃OD, 400 MHz) δ 7.72 (s, 1H),7.45(d, 2H, 7 Hz), 7.39 (t, 2H, 9 Hz, 7.37 (d, 1H, 12 Hz), 7.06 (d, 2H,12Hz), 6.97 (d, 2H, 12Hz), 5.08 (s, 2H), 2.46 (s, 3H). Mass spectrum(ESI, m/z): Calcd. for C₁₉H₁₉N₃OS₂, 370.1 (M+H), found 370.3.

EXAMPLE 252

5-Methylthio-4-{[4-(phenylamino)phenyl]amino}thiophene-2-carboxamidinehydrochloride

a) Methyl5-methylthio-4-{[4-(phenylamino)phenyl]amino}thiophene-2-carboxylate:The same procedure as in Example 250, step (a) was followed using 100 mg(0.3⁷⁴ mmol) of methyl 4-bromo-5-methylthiothiophene-2-carboxylate (asprepared in Example 241, step a), 5.5 mg (6.5 mmol %) of palladium (II)acetate, 21.6 mg (9.3 mmol %) ofracemic-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl, 173.7 mg (0.533mmol) of cesium carbonate, 92.3 mg (0.500 mmol) ofN-phenyl-1,4-phenylenediamine, and 749 μL of toluene, andchromatographed as before using 40% CH₂Cl₂-hexane to afford 58 mg (42%)of methyl5-methylthio-4-{[4-(phenylamino)phenyl]amino}thiophene-2-carboxylate asa brown solid. ¹H-NMR (DMSO-d₆, 400 MHz) δ 7.85 (s, 1H), 7.61 (s, 1H),7.48 (s, 1H), 7.14 (t, 2H, 16 Hz), 6.99 (d, 2H, 16 Hz), 6.90 (q, 4H, 44Hz), 6.70 (t, 2H, 4 Hz), 3.77 (s, 3H), 2.43 (s, 3H).

b) 5-Methylthio-4-[{-(phenylamino)phenyl]amino}thiophene-2-carboxamidinehydrochloride: The same procedure as in Example 250, step (b) wasfollowed using 58 mg (0.156 mmol) of methyl5-methylthio-4-{[4-(phenylamino)phenyl]amino}thiophene-2-carboxylate (asprepared in previous step), 0.783 mL of trimethylaluminum (2.0 M intoluene, 1.56 mmol), 84 mg of ammonium chloride (1.56 mmol) and 10 mL oftoluene, and purified by passing through a pad of silica eluting with50% MeOH—CH₂Cl₂ to afford 50 mg (75%) of the5-methylthio-4-{[4-(phenylamino)phenyl]amino}thiophene-2-carboxamidinehydrochloride as a brown solid. ¹H-NMR (DMSO-d₆, 400 MHz) δ 7.91 (d, 2H,12 Hz), 7.78 (s, 1H), 7.20 (t, 3H, 12 Hz), 7.04-6.94 (m, 5H), 6.71 (m,1H), 2.47 (s, 3H). Mass spectrum (ESI, m/z): Calcd. for C₁₈H₁₈N₄S₂,355.1 (M+H), found 355.4.

EXAMPLE 2534-[(4-Methoxyphenyl)amino]-5-methylthiothiophene-2-carboxamidinehydrochloride

a) Methyl4-[(4-methoxyphenyl)amino]-5-methylthiothiophene-2-carboxylate: To anoven-dried glass vial with stir bar was added a mixture of 120 mg (0.449mmol) of methyl 4-bromo-5-methylthiothiophene-2-carboxylate (as preparedin Example 241, step (a)), 7.1 mg (7 mmol %) of palladium (II) acetate,29.4 mg (10.5 mmol %) ofracemic-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl, 205 mg (0.629 mmol)of cesium carbonate and 69.1 mg (0.561 mmol) of p-anisidine. The vialwas transferred to a glove bag, flushed with dry argon and anhydroustoluene (0.9 mL) was added. The vial was capped with a Teflon-linedscrew cap and heated at 100° C. for 48 h. To the cooled suspension wasadded ethyl acetate (4 mL), the mixture filtered (Celite) washing withethyl acetate (2×2 mL), and the solvents removed in vacuo. The resultingresidue was purified by silica gel preparative thin layer chromatography(40% CH₂Cl₂ in hexane) to afford 83 mg (60%) of the title compound as ayellow oil. ¹H-NMR (CDCl₃, 400 MHz) δ 2.39 (s, 3H), 3.82 (s, 3H), 3.87(s, 3H), 6.03 (s, 1H), 6.89 (m, 2H), 7.03 (m, 2H), 7.58 (s, 1H).

b) 4-[(4-Methoxyphenyl)amino]-5-methylthiothiophene-2-carboxamidinehydrochloride: Trimethylaluminum (2.0 M in toluene, 2 mL,4 mmol) wasadded dropwise to a suspension of ammonium chloride (216 mg, 4 mmol) inanhydrous toluene (1 mL ) under Ar at room temperature. The mixture wasstirred at 25° C. for 30 min and then 80 mg (0.259 mmol) of methyl4-[(4-methoxyphenyl)amino]-5-methylthiothiophene-2-carboxylate (asprepared in previous step) in anhydrous toluene (1 mL ) was added. Thereaction mixture was heated slowly to 100° C. and stirred for 2.5 h. Thecooled mixture was added to a vigorously stirred slurry of silica gel (3g) in chloroform (20 mL). The suspension was filtered washing with MeOH(4×5 mL) and 50% MeOH—CH₂Cl₂ (4×5 mL). The combined washings wereconcentrated and the resulting residue was purified on a 2-g silica SPEcolumn with 5% MeOH—CH₂Cl₂ to afford 50 mg (59%) of the title compoundas an orange solid. ¹H-NMR (DMSO-d₆, 400 MHz) δ 2.44 (s,3H), 3.69 (s,3H), 6.84 (m, 2H), 6.98 (m, 2H), 7.73 (s, 1H), 7.84 (s, 1H), 9.01 (br s,2H), 9.24 (br s, 2H). Mass spectrum (ESI, m/z): Calcd. for C₁₃H₁₅N₃OS₂,294.1 (M+H), found 294.2.

EXAMPLE 2544[(3-Fluoro-4-methylphenyl)amino]-5-methylthiothiophene-2-carboxamidine

a) Methyl4-[(3-fluoro-4-methtylphenyl)amino]-5-methylthiothiophene-2-carboxylate:To an oven-dried glass vial with stir bar was added a mixture of 120 mg(0.449 mmol) of methyl 4-bromo-5-methylthiothiophene-2-carboxylate (asprepared in Example 241, step (a), 41 mg (10 mmol %) oftris-(dibenzylidineacetone)dipalladium, 42 mg (15 mmol %) ofracemic-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl, 205 mg (0.629 mmol)of cesium carbonate and 70 mg (0.56 mmol) of 3-fluoro-4-methylaniline.The vial was transferred to a glove bag, flushed with dry argon andanhydrous toluene (0.9 mL) was added. The vial was capped with aTeflon-lined screw cap and heated at 100° C. for 48 h. To the cooledsuspension was added ethyl acetate (4 mL), the mixture filtered (Celite)washing with ethyl acetate (2×2 mL), and the solvents removed in vacuo.The resulting residue was purified by silica gel preparative thin layerchromatography (10% Et₂O in hexane) to afford 103 mg (78 %) of the titlecompound as a yellow oil ¹H-NMR (CDCl₃, 400 MHz) δ 2.22 (d, 3H, J=1.6Hz), 2.40 (s, 3H), 3.89 (s, 3H), 6.09 (s, 1H), 6.68 (m, 1H), 6.71 (s,1H), 7.08 (m, 1H), 7.72 (s, 1H).

b)4-[(3-Fluoro-4-methylphenyl)amino]-5-methylthiothiophene-2-carboxamidine:The same procedure as in Example 253, step (b) was followed using 103 mg(0.349 mmol) of methyl4-[(3-fluoro-4-methylphenyl)amino]-5-methylthiothiophene-2-carboxylate(as prepared in previous step), 2 mL of trimethylaluminum (2.0 M intoluene, 4 mmol), 216 mg of ammonium chloride (4 mmol) and 2 mL oftoluene, and purified on a 2-g silica SPE column with 5% MeOH—CH₂Cl₂ toafford 45 mg (44%) of the title compound as a yellow foam ¹H-NMR(DMSO-d₆; 400 MHz) δ 2.13 (s, 3H), 2.50 (s, 3H), 6.70 (m, 2H), 7.10 (m,1H), 7.98 (s, 1H), 8.09 (s, 1H), 9.16 (br s, 4H). Mass spectrum (ESI,m/z): Calcd. for C₁₃H₁₄FN₃S₂, 296.1 (M+H), found 296.2.

EXAMPLE 255 4-(indan-5-ylamino)-5-methylthiothiophene-2-carboxamidine

a) Methyl 4-(indan-5-ylamino)-5-methylthiothiophene-2-carboxylate: Thesame procedure as in Example 254, step (a) was followed using 120 mg(0.449 mmol) of methyl 4-bromo-5-methylthiothiophene-2-carboxylate (asprepared in Example 241, step (a), 41 mg (10 mmol %) oftris-(dibenzylidineacetone)dipalladium, 42 mg (15 mmol %) ofracemic-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl, 205 mg (0.629 mmol)of cesium carbonate and 74.8 mg (0.56 mmol) of 5-aminoindan in 900 μL oftoluene, and chromatographed as before using 40% C14₂C₁₂-hexane toafford 100 mg (73%) of the title compound as a yellow resin. ¹H-NMR(CDCl₃, 400 MHz) δ 2.05-2.12 (m, 2H), 2.85-2.90 (m, 4H), 3.86(s, 3H),6,09 (s, 1H), 6.82 (d, 1H, J=8.0 Hz), 6.93 (s, 1H), 7.14 (d, 1H, J=8.0Hz), 7.70 (s, 1H).

b) 4-(Indan-5-ylamino)-5-methylthiothiophene-2-carboxamidine: The sameprocedure as in Example 253, step (b) was followed using 100 mg (0.33mmol) of methyl 4-(indan-5-ylamino)-5-methylthiothiophene-2-carboxylate(as prepared in previous step), 2 mL of trimethylaluminum (2.0 M intoluene, 4 mmol), 216 mg of ammonium chloride (4 mmol) and 2 mL oftoluene, and purified on a 2-g silica SPE column with 5% MeOH—CH₂Cl₂ toafford 65 mg (65% ) of the title compound as a yellow foam. ¹H-NMR(DMSO-d₆, 400 MHz) δ 1.99 (m, 2H), 2.48 (s, 3H), 2.78 (m, 4H), 6.77 (dd,1H, J=8.0, 1.78 Hz), 6.86 (s, 1H), 7.08 (d, 1H, J=8.1 Hz), 7.80 (s, 1H),7.94 (s, 1H), 9.13 (br s, 4H). Mass spectrum (ESI, m/z): Calcd. forC₁₅H₁₇N₃S₂, 304.1 (M+H), found 304.3.

EXAMPLE 2564-[(9-Ethylcarbazol-3-yl)amino]-5-methylthiothiophene-2-carboxamidine

a) Methyl4-[(9-ethylcarbazol-3-yl)amino]-5-methylthiothiophene-2-carboxylate: Thesame procedure as in Example 254, step (a) was followed using 120 mg(0.449 mmol) of methyl 4-bromo-5-methylthiothiophene-2-carboxylate (asprepared in Example 241, step (a), 41 mg (10 mmol %) oftris-(dibenzylidineacetone)dipalladium, 42 mg (15 mmol %) ofracemic-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl , 205 mg (0.629mmol) of cesium carbonate and 118 mg (0.56 mmol) of3-amino-9-ethylcarbazol in 900 μL of toluene, and chromatographed asbefore using 40 % CH₂Cl₂-hexane to afford 80 mg (47%) of the titlecompound as a yellow resin. ¹H-NMR (CDCl₃, 400 MHz) δ 1.46 (t, 3H, J=7.2Hz), 2.44 (s, 3H), 3.85 (s, 3H), 4.39 (q, 2H, J=7.2 Hz), 6.25 (s, 1H),7.24 (m, 1H), 7.28 (s, 1H), 7.40 (m, 2H), 7.49 (m, 1H), 7.61 (s, 1H),7.83 (d, 1H, J=2.1 Hz), 8.06 (d, 1H, J=7.8 Hz).

b)4-[((9-Ethylcarbazol-3-yl)amino]-5-methylthiothiophene-2-carboxamidine:The same procedure as in Example 253, step (b) was followed using 80 mg(0.21 mmol) of methyl4-[(9-ethylcarbazol-3-yl)amino]-5-methylthiothiophene-2-carboxylate (asprepared in previous step), 2 mL of trimethylaluminum (2.0 M in toluene,4 mmol), 216 mg of ammonium chloride (4 mmol) and 2 mL of toluene, andpurified on a 2-g silica SPE column with 5% MeOH—CH₂Cl₂ to afford 56 mg(70%) of the title compound as a yellow foam. ¹H-NMR (DMSO-d₆, 400 MHz)δ 1.31 (t, 3H, J=7.0 Hz),2.50 (s, 3H), 4.42 (q, 2H, J=7.0Hz), 7.14 (m,1H), 7.27 (dd, 1H, J=8.7,2.1 Hz), 7.43 (m, 1H), 7.56 (m, 2H), 7.82 (d,1H, J=2.0 Hz), 7.87 (s, 1H), 7.92 (s, 1H), 8.10 (d, 1H, J=7.7 Hz), 9.11(br s, 4H). Mass spectrum (ESI, m/z): Calcd. for C₂₀H₂₀N₄S₂, 381.1(M+H), found 381.3.

EXAMPLES 257 AND 2585-Methylthio-4-{[(4-phenylphenyl)sulfonyl]amino}thiophene-2-carboxamidinetrifluoroacetate4-{Bis[(4-phenylphenyl)sulfonyl]amino}-5-methylthiothiophene-2-carboxamidinetrifluoroacetate

a) Methyl 5-methylthio-4-[(phenylsulfonyl)amino]thiophene-2-carboxylateand methyl4-(bis[(4-phenylphenyl)sulfonyl]amino}-5-methylthiothiophene-2-carboxylate:To an oven-dried round bottom flask with stir bar was added a mixture of50 mg (0.24 mmol) of methyl 4-amino-5-methylthiothiophene-2-carboxylate(as prepared in Example 202), 68 mg (0.27 mmol) of 4-biphenylsulfonylchloride and 50 mg (0.49 mmol) of 4-dimethylaminopyridine. The flask wasflushed with dry argon and anhydrous acetonitrile (3 mL) was added. Thereaction was refluxed for 3 hours and then the solvent was removed invacuo. The crude of the reaction was extracted with ethyl acetate (2×25mL) and IN HCl (50 mL), The organic layer was collected, dried (Na₂SO₄),filtered and concentrated under vacuum to yield a foam that waschromatographed on silica with 30% ethyl ether-hexane to obtain 143 mgof a mixture of methyl5-methylthio-4-[(phenylsulfonyl)amino]thiophene-2-carboxylate and methyl4-{bis[(4-phenylphenyl)-sulfonyl]amino}-5-methylthiothiophene-2-carboxylate.This mixture was used in the next reaction without further purification.Mass spectrum (ESI, m/z): Calcd. for C₁₉H₁₇NO₄S₃, 420.0 (M+H), found419.7.

b)5-Methylthio-4-({[(4-phenylphenyl)sulfonyl]amino}thiophene-2-carboxamidinetrifluoroacetate and4-{bis[(4-phenylphenyl)sulfonyl]-amino}-5-methylthiothiophene-2-carboxamidinetrifluoroacetate: Trimethylaluminum (2.0 M in toluene, 1.36 mL, 2.72mmol) was added dropwise to a suspension of ammonium chloride (155 mg,2.89 mmol) in anhydrous toluene (2.0 mL) under Ar at 0° C. The mixturewas stirred at 25° C. for 30 min and then 143 mg of a mixture of methyl5-methylthio-4-[(phenylsulfonyl)amino]thiophene-2-carboxylate and methyl4-{bis[(4-phenylphenyl)sulfonyl]amino}-5-methylthiothiophene-2-carboxylate (as prepared in previous step) inanhydrous toluene (2.0 mL) was added. The reaction mixture was heatedslowly to 100° C. and stirred for 4 h. The cooled mixture was added to avigorously stirred slurry of silica gel (3 g) in chloroform (15 mL). Thesuspension was filtered (Celite) washing with 25% MeOH—CH₂Cl₂ (2×5 mL),50% MeOH—CH₂Cl₂ (2×5 mL) and 75% MeOH—CH₂Cl₂ (2×5 mL). The combinedwashings were concentrated and the resulting residue was purified on a10-g silica SPE column with a gradient of 10-15% MeOH—CH₂Cl₂ saturatedwith ammonia to afford 66 mg of a mixture of the title compounds as ayellow solid. This mixture was chromatographed by preparative reversephase HPLC performed with a Rainin SD-1 Dynamax system and a 2-in. C18reverse phase Dynamax 60A column using a gradient of 30% MeOH/0.1% TFAin water to 100% MeOH and a flow rate of 50 mL/ min. to yield 15 mg5-methylthio-4-{[(4-phenylphenyl)sulfonyl]amino}thiophene-2-carboxamidine trifluoroacetate; mass spectrum (ESI, m/z):Calcd. for C₁₈H₁₇N₃O₂S₃, 404.0 (M+H), found 404.1; and 11 mg of4-{bis[(4-phenylphenyl)sulfonyl]amino}-5-methylthiothiophene-2-carboxamidinetrifluoroacetate. Mass spectrum (ESI, m/z): Calcd. for C₃₀H₂₅N₃O₄S₄,619.8 (M+H), found 620.2.

EXAMPLES 259 TO 282

The same methods as for Examples 257 and 258 were used to synthesize thefollowing compounds:

Mass spec, ESI, m/z Examp Reagent Compound Formula Calc, M + H Found 2591-Naphthalenesulfonyl5-Methylthio-4-[(2-naphthylsulfonyl)amino]thiophene-2-carbo-C16H15N3O2S3 378.0 378.1 chloride xamidine 260 1-Naphthalenesulfonyl4-[Bis(2-naphthylsulfonyl)amino]-5-methylthiothiophene-2-carbo-C26H21N3O4S4 568.0 568.1 chloride xamidine 261 7-Bromonaphthalene4-{[(6-Bromo(2-naphthyl))sulfonyl]amino}-5-methylthiothiophene-2-C16H14BrN3O2S3 455.9 * sulfonyl chloride carboxamidine 2627-Bromonaphthalene4-{Bis[(6-bromo(2-naphthyl))sulfonyl]amino}-5-methylthiothio-C26H19Br2N3O4S4 723.9 * sulfonyl chloride phene-2-carboxamidine 2632-Naphthalenesulfonyl5-Methylthio-4-[(naphthylsulfonyl)amino]thiophene-2-carbo- C16H15N3O2S3378.0 378.1 chloride xamidine 264 2-Naphthalenesulfonyl4-[Bis(naphthylsulfonyl)amino]-5-methylthiothiophene-2-carbo-C26H21N3O4S4 568.7 568.3 chloride xamidine 265 o-Toluenesulfonyl4-{[(2-Methylphenyl)sulfonyl]amino}-5-methylthiothiophene-2-C13H15N3O2S3 342.4 342.1 chloride carboxamidine 266 o-Toluenesulfonyl4-{Bis[(2-methylphenyl)sulfonyl]amino}-5-methylthiothiophene-2-C20H21N3O4S4 496.6 496.1 chloride carboxamidine 267 m-Toluenesulfonyl4-{[(3-Methylphenyl)sulfonyl]amino}-5-methylthiothiophene-2-C13H15N3O2S3 342.0 342.1 chloride carboxamidine 268 m-Toluenesulfonyl4-{Bis[(3-methylphenyl)sulfonyl]amino}-5-methylthiothiophene-2-C20H21N3O4S4 496.6 496.0 chloride carboxamidine 269 p-Toluenesulfonyl4-{[(4-Methylphenyl)sulfonyl]amino}-5-methylthiothiophene-2-C13H15N3O2S3 342.0 342.1 chloride carboxamidine 270 p-Toluenesulfonyl4-{Bis[(4-methylphenyl)sulfonyl]amino }-5-methylthiothiophene-2-C20H21N3O4S4 496.6 496.1 chloride carboxamidine 271 α-Toluenesulfonyl5-Methylthio-4-{[benzylsulfonyl]amino}-thiophene-2-carboxamidineC13H15N3O2S3 342.0 342.1 chloride 272 4-Methoxybenzene-4-{[(4-Methoxyphenyl)sulfonyl]amino}-5-methylthiothiophene-2-C13H15N3O3S3 358.0 358.1 sulfonyl chloride carboxamidine 2734-Methoxybenzene-4-{Bis[(4-methoxyphenyl)sulfonyl]amino}-5-methylthiothiophene-2-C20H21N3O6S4 528.0 528.0 sulfonyl chloride carboxamidine 2744-Iodobenzenesulfonyl4-{[(4-Iodophenyl)sulfonyl]amino}-5-methylthiothiophene-2-carbo-C12H121N3O2S3 453.9 454.0 chloride xamidine 275 3,4-Dimethoxy-4-{[(3,4-Dimethoxyphenyl)sulfonyl]amino}-5-methylthiothiophene-2-C14H17N3O4S3 388.0 388.1 benzenesulfonyl carboxamidine chloride 2763,4-Dimethoxy-4-{bis[(3,4-Dimethoxyphenyl)sulfonyl]amino}-5-methylthiothio-C22H25N3O8S4 588.0 588.1 benzenesulfonyl phene-2-carboxamidine chloride277 2-Chlorobenzene-4-{[(2-Chlorophenyl)sulfonyl]amino}-5-methylthiothiophene-2-C12H12C1N3O2S3 361.9 362.1 sulfonyl chloride carboxamidine 2783-Chlorobenzene-4-{[(3-Chlorophenyl)sulfonyl]amino}-5-methylthiothiophene-2-C12H12C1N3O2S3 361.9 362.1 sulfonyl chloride carboxamidine 2793-Chlorobenzene-4-{Bis[(3-chlorophenyl)sulfonyl]amino}-5-methylthiothiophene-2-C18H15C12N3O4S4 535.9 537.9 sulfonyl chloride carboxamidine 2804-Chlorobenzene-4-{[(4-Chlorophenyl)sulfonyl]amino}-5-methylthiothiophene-2-C12H12C1N3O2S3 361.9 362.1 sulfonyl chloride carboxamidine 2814-Chlorobenzene-4-{Bis[(4-chlorophenyl)sulfonyl]amino}-5-methylthiothiophene-2-C18H15C12N3O4S4 535.9 * sulfonyl chloride carboxamidine 282Benzenesulfonyl5-Methylthio-4-[(phenylsulfonyl)amino]-thiophene-2-carboxamidineC12H13N3O2S3 328.0 328.1 chloride 283 Benzenesulfonyl4-[Bis(phenylsulfonyl)amino]-5-methylthiophene-2-carboxamidineC18H17N3O4S4 468.0 467.9 chloride 284 4-tert-Butylbenzene-4-({[4-(Tert-butyl)phenyl]sulfonyl}amino)-5-methylthiothiophene-2-C16H21N3O2S3 384.0 384.2 sulfonyl chloride carboxamidine 2854-tert-Butylbenzene-4-(Bis{[4-(tert-butyl)phenyl]sulfonyl}amino)-5-methylthiothiophene-C26H33N3O4S4 580.1 580.2 sulfonyl chloride 2-carboxamidine 286Trans-β-styrene4-{[((1E)-2-Phenylvinyl)sulfonyl]amino}-5-methylthiothiophene-2-C14H15N3O2S3 354.0 * sulfonyl chloride carboxamidine 2874-benzensulfonyl-5-Methylthio-4-({[4-(phenylsulfonyl)(2-thienyl)]sulfonyl}amino)-C16H15N3O4S5 473.9 474.1 thiophene-2-sulfonyl thiophene-2-carboxamidinechloride * Mass spectral data inconclusive.

EXAMPLE 288 5-Methylthio-4-phenoxythiophene-2-carboxamidinetrifluoroacetate.

a) Methyl 5-methylthio-4-phenoxythiophene-2-carboxylate: To anoven-dried round bottom flask with stir bar was added a mixture of 100mg (0.37 mmol) of methyl 4-bromo-5-methylthiothiophene-2-carboxylate (asprepared in Example 241), 20 mg of Cu (0)(Brewster, R. Q. and GroeningT., Organic Syntheses, Vol. II, Note 1, pp 445-446) and 42 mg (0.46mmol) of phenol. The flask was flushed with dry argon and anhydroustetrahydrofuran (5 mL) was added. The reaction was refluxed for 48 hoursand then the solvent was removed in vacuo. The resulting residue waspurified on a 10-g silica SPE column with a gradient of 50-100%CH₂Cl₂-hexane to yield 48 mg ofmethyl5-methylthio-4-phenoxythiophene-2-carboxylate (37%). ¹H-NMR(CDCl₃, 400 MHz) δ 7.39 (s, 1H), 7.32 (m, 2H), 7.09 (m, 2H), 6.97 (d,1H, J=8.4 Hz), 3.86 (s, 3H) and 2.49 (s, 3H).

b) 5-Methylthio-4-phenoxythiophene-2-carboxamidine trifluoroacetate: Thesame procedure as in Example 257, step (b) was followed using 48.0 mg(0.17 mmol) of methyl 5-methylthio-4-phenoxythiophene-2-carboxylate (asprepared in the step before), 78 mg of ammonium chloride (1.5 mmol),0.68 ml of trimethylaluminum (2.0 M in toluene, 1.3 mmol) and 3 ml ofanhydrous toluene and chromatographed as before using preparativereverse phase HPLC performed with a Rainin SD-1 Dynamax system and a2-in. C18 reverse phase Dynamax 60A column using a gradient of 30% MeOH/0.1% TFA in water to 100% MeOH and a flow rate of 50 mL/ min. ¹H-NMR(CD₃OD, 400 MHz) δ 7.66 (s, 1H), 7.39 (t, 2H, J=7.5 Hz), 7.17 (t, 2H,J=7.4 Hz), 7.02 (d, 1H, J=7.7 Hz) and 2.58 (s, 3H). Mass spectrum (ESI,m/z): Calcd. C₁₂H₁₂N₂OS_(2, 265.0) (M+H), found 262.2.

EXAMPLE 289 5-Methylthio-4-(phenylsulfonyl)thiophene-2-carboxamidinetrifluoroacetate.

a) 4-Bromo-5-methylthiothiophene-2-carboxylic acid: To 1.0 g (3.7 mmol)of methyl 4-bromo-5-methylthiothiophene-2-carboxylate (as prepared inExample 241, step (a) dissolved in 25 ml of MeOH was added 450 mg ofNaOH dissolved in 10 ml of H₂O. The reaction was stirred for 5 hours atroom temperature, and then the solvents were removed under vacuum. Theresidue of the reaction was extracted with ethyl acetate (2×50 mL) and1N HCl. The organic layer was collected, dried (Na₂SO₄), filtered andconcentrated under vacuum to yield 833 mg (89%) of4-bromo-5-methylthiothiophene-2-carboxylic acid as a white solid.

b) 5-Methylthio-4-(phenylsulfonyl)thiophene-2-carboxylic acid: To anoven-dried round bottom flask with stir bar was added 100 mg (0.39 mmol)4-bromo-5-methylthiothiophene-2-carboxylic acid (as prepared in Examplebefore). The flask was flushed with dry argon and anhydroustetrahydrofuran (3 mL) was added. Then the solution was cooled at −78°C. before adding 511 μL of tert-butyl lithium (0.87 mmol, 1.7 M intetrahydrofuran). The mixture was stirred for a period of 45 minutes and77 mg of benzenesulfonyl flouride (0.39 mmol) was added and the reactionwas allowed to rise to room temperature. The reaction was stirred for 12hours and then quenched carefully with H₂O. The solvents were removedunder vacuum and the residue of the reaction was extracted with ethylacetate (2×50 ml) and 1N HCl. The organic layer was collected, dried(Na₂SO₄), filtered and concentrated under vacuum to yield 130 mg of asolid. This solid was used in the next step without furtherpurification.

c) Methyl 5-methylthio-4-(phenylsulfonyl)thiophene-2-carboxylate: To asolution of 25 mg of the mixture from the previous step dissolved in 3mL of MeOH wa added dropwise 397 μL of trimethylsilyldiazomethane (0.79mmol, 2 M solution in hexanes) and the reaction was stirred for a periodof 1 hour. The solvents were removed under vacuum. The resulting residuewas purified on a 10-g silica SPE column with a gradient of 50-100%ethyl acetate-hexane to yield 13.8 mg of methyl5-methylthio-4-(phenylsulfonyl)thiophene-2-carboxylate. Mass spectrum(ESI, m/z): Calcd. C₁₃H₁₂O₄S₃, 329.0 (M+H), found 329.0.

d) 5-Methylthio-4-(phenylsulfonyl)thiophene-2-carboxamidinetrifluoroacetate: The same procedure as in Example 257, step (b) wasfollowed using 13.8 mg (0.044 mmol) of methyl5-methylthio-4-(phenylsulfonyl)thiophene-2-carboxylate (as prepared inthe step before), 20 mg of ammonium chloride (0.376 mmol), 0.176 ml oftrimethylaluminum (2.0 M in toluene, 0.353 mmol) and 3 ml of anhydroustoluene and chromatographed as before by preparative reverse phase HPLCperformed with a Rainin SD-1 Dynamax system and a 2-in. C18 reversephase Dynamax 60A column using a gradient of 30% MeOH /0.1% TFA in waterto 100% MeOH and a flow rate of 50 mL/ min to yield 2.3 mg of5-methylthio-4-(phenylsulfonyl)thiophene-2-carboxamidine. ¹H-NMR (CD₃OD,400 MHz) δ 8.42 (s, 1H), 8.04 (m, 2H), 7.70 (m, 2H), 7.62 (m, 1H) and2.70 (s, 3H). Mass spectrum (ESI, m/z): Calcd. C₁₂Hi₂N₂O₂S₃, 313.0(M+H), found 313.2.

EXAMPLE 290 TABLET PREPARATION

Tablets containing 25.0, 50.0, and 100.0 mg, respectively, of thefollowing active compounds are prepared as illustrated below:

a. 4-(4-methylthiazol-2-yl)-5-methylthiothiophene-2-carboxamidine;

b.4-[4-(4-phenylphenyl)thiazol-2-yl]-5-methylthiothiophene-2-carboxamidine.

TABLET FOR DOSES CONTAINING FROM 25-100 MG OF THE ACTIVE COMPOUNDAmount-mg Active Compound 25.0 50.0 100.00 Microcrystalline cellulose37.25 100.0 200.0 Modified food corn starch 37.25 4.25 8.5 Magnesiumstearate 0.50 0.75 1.5

All of the active compound, cellulose, and a portion of the cornstarchare mixed and granulated to 10% corn starch paste. The resultinggranulation is sieved, dried and blended with the remainder of the cornstarch and the magnesium stearate. The resulting granulation is thencompressed into tablets containing 25.0, 50.0, and 100.0 mg,respectively, of active ingredient per tablet.

EXAMPLE 291 INTRAVENOUS SOLUTION PREPARATION

An intravenous dosage form of the above-indicated active compounds isprepared as follows:

Active Compound 0.5-10.0 mg Sodium Citrate 5-50 mg Citric Acid 1-15 mgSodium Chloride 1-8 mg Water for Injection (USP) q.s. to 1 ml

Utilizing the above quantities, the active compound is dissolved at roomtemperature in a previously prepared solution of sodium chloride, citricacid, and sodium citrate in Water for Injection (USP, see page 1636 ofUnited States Pharmacopeia/National Formulary for 1995, published byUnited States Pharmacopeial Convention, Inc., Rockville, Md. (1994).

EXAMPLE 292 In vitro Inhibition of Purified Enzymes

Reagents: All buffer salts were obtained from Sigma Chemical Company(St. Louis, Mo.), and were of the highest purity available. The enzymesubstrates, N-benzoyl-Phe-Val-Arg-p-nitroanilide (Sigma B7632),N-benzoyl-Ile-Glu-Gly-Arg-p-nitroanilide hydrochloride (Sigma B2291),N-p-tosyl-Gly-Pro-Lys-p-nitroanilide (Sigma T6140),N-succinyl-Ala-Ala-Pro-Phe-p-nitroanilide (Sigma S7388) andN-CBZ-Val-Gly-Arg-p-nitroanilide (Sigma C7271) were obtained from Sigma.N-Succinyl-Ala-Ala-Pro-Arg-p-nitroanilide (BACHEM L-1720) andN-succinyl-Ala-Ala-Pro-Val-p-nitroanilide (BACHEM L-1770) were obtainedfrom BACHEM (King of Prussia, Pa.).

Human α-thrombin, human factor Xa and human plasmin were obtained fromEnzyme Research Laboratories (South Bend, Ind.). Bovine α-chymotrypsin(Sigma C4129), bovine trypsin (Sigma T8642) and human kidney cellurokinase (Sigma U5004) were obtained from Sigma. Human leukocyteelastase was obtained from Elastin Products (Pacific, Mo.). K_(i)Determinations: All assays are based on the ability of the test compoundto inhibit the enzyme catalyzed hydrolysis of a peptide p-nitroanilidesubstrate. In a typical K_(i) determination, substrate is prepared inDMSO, and diluted into an assay buffer consisting of 50 mM HEPES, 200 mMNaCl, pH 7.5. The final concentrations for each of the substrates islisted below. In general, substrate concentrations are lower than theexperimentally determined value for K_(m). Test compounds are preparedas a 1.0 mg/mL solution in DMSO. Dilutions are prepared in DMSO yielding8 final concentrations encompassing a 200 fold concentration range.Enzyme solutions are prepared at the concentrations listed below inassay buffer.

In a typical K_(i) determination, into each well of a 96 well plate ispipetted 280 μL of substrate solution, 10 μL of test compound solution,and the plate allowed to thermally equilibrate at 37° C. in a MolecularDevices plate reader for >15 minutes. Reactions were initiated by theaddition of a 10 μL aliquot of enzyme and the absorbance increase at 405nm is recorded for 15 minutes. Data corresponding to less than 10% ofthe total substrate hydrolysis were used in the calculations. The ratioof the velocity (rate of change in absorbance as a function of time) fora sample containing no test compound is divided by the velocity of asample containing test compound, and is plotted as a function of testcompound concentration. The data are fit to a linear regression, and thevalue of the slope of the line calculated. The inverse of the slope isthe experimentally determined K_(i) value.

Thrombin: Thrombin activity was assessed as the ability to hydrolyze thesubstrate N-succinyl-Ala-Ala-Pro-Arg-p-nitroanilide. Substrate solutionswere prepared at a concentration of 32 μM (32 μ<<Km=180 μM) in assaybuffer. Final DMSO concentration was 4.3%. Purified human α-thrombin wasdiluted into assay buffer to a concentration of 15 nM. Final reagentconcentrations were: [thrombin]=0.5 nM, [substrateN-succinyl-Ala-Ala-Pro-Arg-p-nitroanilide]=32 μM.

Factor X [FXa]: FXa activity was assessed as the ability to hydrolyzethe substrate N-benzoyl-Ile-Glu-Gly-Arg-p-nitroanilide hydrochloride.Substrate solutions were prepared at a concentration of 51 μM(51<<K_(m)=1.3 mM) in assay buffer. Final DMSO concentration was 4.3%.Purified activated human Factor X was diluted into assay buffer to aconcentration of 300 nM. Final reagent concentrations were: [FXa]=10 nM,[N-benzoyl-De-Glu-Gly-Arg-p-nitroanilide hydrochloride]=51 μM.

Plasmin: Plasmin activity was assessed as the ability to hydrolyze theN-p-Tosyl-Gly-Pro-Lys-p-nitroanilide. Substrate solutions were preparedat a concentration of 37 μM (37 μM<<K_(m)=243 μM) in assay buffer. FinalDMSO concentration was 4.3%. Purified human plasmin was diluted intoassay buffer to a concentration of 240 nM. Final reagent concentrationswere: [Plasmin]=8 nM, [N-p-Tosyl-Gly-Pro-Lys-p-nitroanilide]=37 μM.

Chymotrypsin: Chymotrypsin activity was assessed as the ability tohydrolyze N-succinyl-Ala-Ala-Pro-Phe-p-nitroanilide. Substrate solutionswere prepared at a concentration of 14 μM (14 μM K_(m)=62 μM) in assaybuffer. Final DMSO concentration was 4.3%. Purified bovine chymotrypsinwas diluted into assay buffer to a concentration of 81 nM. Final reagentconcentrations were: [Chymotrypsin]=2.7 nM,[N-succinyl-Ala-Ala-Pro-Phe-p-nitroanilide]=14 μM.

Trypsin: Trypsin activity was assessed as the ability to hydrolyzeN-benzoyl-Phe-Val-Arg-p-nitroanilide. Substrate solutions were preparedat a concentration of 13 μM (13 μM<<K_(m) =291 μM) in assay buffer.Final DMSO concentration was 4.3%. Purified bovine trypsin was dilutesinto assay buffer to a concentration of 120 nM. Final reagentconcentrations were: [Trypsin]=4 nM,[N-benzoyl-Phe-Val-Arg-p-nitroanilide]=13 μM.

Elastase: Elastase activity was assessed as the ability to hydrolyzeN-succinyl-Ala-Ala-Pro-Val-p-nitroanilide. Substrate solutions wereprepared at a concentration of 19 μM (19 μM<<K_(m)=89 μM) in assaybuffer. Final DMSO concentration was 4.3%. Purified human leukocyteelastase was diluted into assay buffer to a concentration of 750 nM.Final reagent concentrations were: [Elastase]=25 nM,[N-succinyl-Ala-Ala-Pro-Val-p-nitroanilide]=19 μM.

Urokinase: Urokinase activity was assessed as the ability to hydrolyzeN-CBZ-Val-Gly-Arg-p-nitroanilide. Substrate solutions were prepared at aconcentration of 100 μM (100 μM<K_(m)=1.2 mM) in assay buffer. FinalDMSO concentration was 4.3%. Purified human kidney urokinase was dilutedinto assay buffer to a concentration of 1.2 μM. Final reagentconcentrations were: [Urokinase]=40 nM, andN-CBZ-Val-Gly-Arg-p-nitroanilide]=100 mM.

The results of exemplary assays are shown in the following table.

Protease Inhibition Data Protease Ki Example # micromolar Trypsin 0.8588 Trypsin 0.474 52 Factor Xa 2.73 94 Factor Xa 3.00 119 Chymo- 4.90 11trypsin tPA 9.49 1 Plasmin 7.31 12 CIS 0.940 283

Additionally, the following compounds have Ki values in the range of0.016 to 3.5 micromolar for uPA:

Ex. #28, 40, 53, 79, 84, 89, 131, 138, 139, 140, 143, 145, 172, 187,200, 204, 206, 208, 213, 220, 222, 223, 227, 233, 235, 239, 260, 281 and288.

The results indicate that the compounds of the present invention areinhibitors of proteases, including urokinase.

Having now fully described this invention, it will be understood tothose of ordinary skill in the art that the same can be performed withina wide and equivalent range of conditions, formulations, and otherparameters without affecting the scope of the invention or anyembodiment thereof. All patents and publications cited herein are fullyincorporated by reference herein in their entirety.

What is claimed is:
 1. A method of treating a patient (i) with a diseasecaused by aberrant proteolysis, excessive cell growth or cell migrationresulting from thrombolytic therapy, percutaneous transluminal coronaryangioplasty, hip replacement, or coronary bypass; (ii) with a diseasecaused by aberrant proteolysis, excessive cell growth or cell migrationselected from deep vein thrombosis, disseminated intravascularcoagulopathy which occurs during septic shock, viral infection, cancer,myocardial infarction, stroke, fibrin formation in the eye, retinopathy,adult respiratory distress syndrome, inflammation, a wound, reperfusiondamage, atherosclerosis, or restenosis following balloon angioplasty,atherectomy or arterial stent replacement; (iii) in need of regulatingthe promotion of neointimal formation; or (iv) in need of regulatingextracellular matrix proteolysis, tissue remodeling, or cell migration,comprising administering to a patient in need thereof an effectiveamount of a compound of Formula I:

 or a solvate, hydrate or pharmaceutically-acceptable salt thereof,wherein: X is sulfur; R⁷ is hydrogen, alkyl, aralkyl,hydroxy(C₃₋₄)alkyl, alkoxy(C₃₋₄)alkyl; Y is a covalent bond, CH₂ or NH;Z is NR⁵R⁶; R¹ is a hydrogen, amino, hydroxy, halogen, cyano, C₁₋₄alkyl,—CH₂R where R is hydroxyamino, or C₁₋₃ alkoxy; R² and R³ areindependently: i. hydrogen; ii. halogen; iii. hydroxy; iv. nitro; v.cyano; vi. amino, monoalkylamino, dialkylamino, monoarylamino,diarylamino, monoalkylmonoarylamino, monoaralkylamino, diaralkylamino,alkarylamino, alkoxycarbonylamino, aralkoxycarbonylamino,aryloxycarbonylamino, alkylsulfonylamino, aralkylsulfonylamino,arylsulfonylamino, formylamino, acylamino, H(S)CNH—, or thioacylamino;vii. aminocarbonyl, monoalkylaminocarbonyl, dialkylaminocarbonyl, acyl,arylaminocarbonyl, or aminoacyl; viii. aminothiocarbonyl,monoalkylaminothiocarbonyl, dialkylaminothiocarbonyl,thioacyl, oraminothioacyl; ix. aminocarbonylamino, monoalkylaminocarbonylamino,dialkylaminocarbonylamino, monoarylaminocarbonylamino,diarylaminocarbonylamino, monoaralkylaminocarbonylamino, ordiaralkylaminocarbonylamino, x. aminocarbonyloxy,monoalkylaminocarbonyloxy, dialkylaminocarbonyloxy,monoarylaminocarbonyloxy, diarylaminocarbonyloxy,monoaralkylaminocarbonyloxy, or diaralkylaminocarbonyloxy, xi.aminosulfonyl, monoalkylaminosulfonyl, dialkylaminosulfonyl,monoarylaminosulfonyl, diarylaminosulfonyl, or monoaralkylaminosulfonyl,or diaralkylaminosulfonyl, xii. alkoxy or alkylthio, wherein said alkylportion of said alkoxy or alkylthio group may be optionally substituted;xiii. aralkoxy, aryloxy, aralkylthio, or arylthio, wherein the arylportion of said aralkoxy, aryloxy, aralkylthio or arylthio group may beoptionally substituted; xiv. alkylsulfonyl, wherein the alkyl portionmay be optionally substituted; xv. aralkylsulfonyl, or arylsulfonyl,wherein the aryl portion of each group can be optionally substituted,xvi. alkenyl or alkynyl; xvii. optionally substituted aryl; xviii.optionally substituted alkyl; xix. optionally substituted aralkyl; xx.optionally substituted heterocycle; or xxi. optionally substitutedcycloalkyl; and R⁴, R⁵ and R⁶ are independently hydrogen, C₁₋₄ alkyl,aryl, hydroxyalkyl, aminoalkyl, monoalkylamino(C₂₋₁₀)alkyl,dialkylamino(C₂₋₁₀)alkyl, carboxyalkyl, cyano, amino, alkoxy, orhydroxy.
 2. A method according to claim 1, wherein said compound is oneof: 5-methylthio-4-(6-quinolylamino)thiophene-2-carboxamidine;5-methylthio-4-[(3-phenylphenyl)amino]thiophene-2-carboxamidine;5-methylthio-4-(3-quinolylamino)thiophene-2-carboxamidine;5-methylthio-4-(pyrimidin-2-ylamino)thiophene-2-carboxamidine;4-[(4-cyclohexylphenyl)amino]-5-methylthiothiophene-2-carboxamidine;methyl 4-amino-5-methylthiothiophene-2-carboxylate; methyl4-[(aminothioxomethyl)amino]-5-methylthiothiophene-2-carboxylate;5-methylthio-4-[(4-phenyl(1,3-thiazol-2-yl))amino]thiophene-2-carboxamidine;5-methylthio-4-{[4-(4-phenylphenyl)(1,3thiazol-2-yl)]amino}thiophene-2-carboxamidine;4-[(5-methyl-4-phenyl(1,3-thiazol-2-yl))amino]-5-methylthiothiophene-2-carboxamidine;4-{[4-hydroxy-4-(trifluoromethyl)(1,3-thiazolin-2-yl)]amino)}-5-methylthiothiophene-2-carboxamidine;5-methylthio-4-(2-naphthylamino)thiophene-2-carboxamidine;4-[(4-chlorophenyl)amino]-5-methylthiothiophene-2-carboxamidine;4-[(3-methylphenyl)amino]-5-methylthiothiophene-2-carboxamidine;4-[(3-methoxyphenyl)amino]-5-methylthiothiophene-2-carboxamidine;4-{[3-(methylethyl)phenyl]amino]}-5-methylthiothiophene-2-carboxamidine;5-methylthio-4-[(3-nitrophenyl)amino]thiophene-2-carboxamidine;4-{[4-(methylethyl)phenyl]amino}-5-methylthiothiophene-2-carboxamidine;4-[(3,4-dimethylphenyl)amino]-5-methylthiothiophene-2-carboxamidine;5-methylthio-4-[(4-phenylphenyl)amino]thiophene-2-carboxamidine;4-[(3-fluoro-4-phenylphenyl)amino]-5-methylthiothiophene-2-carboxamidine;4-(2H-benzo[d]1,3-dioxolen-5-ylamino)-5-methylthiothiophene-2-carboxamidine;4-[(4-butylphenyl)amino]-5-methylthiothiophene-2-carboxamidine;5-methylthio-4-[benzylamino]thiophene-2-carboxamidine;4-(indan-5-ylamino)-5-methylthiothiophene-2-carboxamidine;4-(2,3-dihydrobenzo[b]furan-5-ylamino)-5-methylthiothiophene-2-carboxamidine;5methylthio-4-[(2-phenylimidazol-4-yl) amino]thiophene-2-carboxamindine;5-methylthio-4-[(2-quinolylmethyl)amino]thiophene-2-carboxamidine;4-{[(3-hydroxyphenyl)methyl]amino)}-5-methylthiothiophene-2-carboxamidine;5-methylthio-4-(phenylcarbonylamino)thiophene-2-carboxamidine;4-((2E)-3-phenylprop-2-enoylamino)-5-methylthiothiophene-2-carboxamidine;4-[(4-chlorophenyl)carbonylamino]-5-methylthiothiophene-2-carboxamidine;4-(cyclohexylcarbonylamino)-5-methylthiothiophene-2-carboxamidine;methyl4-[(4-methyl-3-nitrophenyl)carbonylamino]-5-methylthiothiophene-2-carboxylate;4-(2-furylcarbonylamino)-5-methylthiothiophene-2-carboxamidine;4-(2,2-dimethylpropanoylamino)-5-methylthiothiophene-2-carboxamidine;4-{[5-(3,5-dichlorophenoxy)(2-furyl)]carbonylamino}-5-methylthiothiophene-2-carboxamidine;5-methylthio-4-(1-naphthylcarbonylamino)-thiophene-2-carboxamidine;5-methylthio-4-(2-quinolylcarbonylamino)thiophene-2-carboxamidine;4-[(3-methoxyphenyl)carbonylamino]-5-methylthiothiophene-2-carboxamidine;4-[2-(2-hydroxy-5-methoxyphenyl)acetylamino]-5-methylthiothiophene-2-carboxamidine;4-[(4-ethoxyphenyl)carbonylamino]-5-methylthiothiophene-2-carboxamidine;5-methylthio-4-(2-phenoxyacetylamino)-thiophene-2-carboxamidine;4-[(3-methylphenyl)carbonylamino]-5-methylthiothiophene-2-carboxamidine;5-methylthio-4-{[3-(phenylmethoxy)phenyl]amino}thiophene-2-carboxamidine;5-methylthio-4-[(3-phenoxyphenyl)amino]thiophene-2-carboxamidine;5-methylthio-4-[(4-phenoxyphenyl)amino]thiophene-2-carboxamidine;4-[(2-methoxyphenyl)amino]-5-methylthiothiophene-2-carboxamidine;4-[(2-methylphenyl)amino]-5-methylthiothiophene-2-carboxamidine;4-[(3-chlorophenyl)amino]-5-methylthiothiophene-2-carboxamidine;4-(methylphenylamino)-5-methylthiothiophene-2-carboxamidine;5-methyl-4-(phenylamino)thiophene-2-carboxamidine;4-{[4-(dimethylamino)phenyl]amino}-5-methylthiothiophene-2-carboxamidine;4-[(4-ethylphenyl)amino]-5-methylthiothiophene-2-carboxamidine;5-methylthio-4-{[4-(phenylmethoxy)phenyl]amino}thiophene-2-carboxamidine;5-methylthio-4-{[4-(phenylamino)phenyl]amino}thiophene-2-carboxamidine;4-[(4-methoxyphenyl)amino]-5-methylthiothiophene-2-carboxamidine;4-[(3-fluoro-4-methylphenyl)amino]-5-methylthiothiophene-2-carboxamidine;4-(indan-5-ylamino)-5-methylthiothiophene-2-carboxamidine;4-[(9-ethylcarbazol-3-yl)amino]-5-methylthiothiophene-2-carboxamidine;5-methylthio-4-{[(4-phenylphenyl)sulfonyl]amino}thiophene-2-carboxamidine;4-{bis[(4-phenylphenyl)sulfonyl]amino}-5-methylthiothiophene-2-carboxamidine;5-methylthio-4-[(2-naphthylsulfonyl)amino]thiophene-2-carboxamidine;4-[bis(2-naphthylsulfonyl)amino]-5-methylthiothiophene-2-carboxamidine;4-{[(6-bromo(2-naphthyl))sulfonyl]amino}-5-methylthiothiophene-2-carboxamidine;4-{bis[(6-bromo(2-naphthyl))sulfonyl]amino}-5-methylthiothiophene-2-carboxamidine;5-methylthio-4-[(naphthylsulfonyl)amino]thiophene-2-carboxamidine;4-[bis(naphthylsulfonyl)amino]-5-methylthiothiophene-2-carboxamidine;4-{[(2-methylphenyl)sulfonyl]amino}-5-methylthiothiophene-2-carboxamidine;4-{bis[(2-methylphenyl)sulfonyl]amino}-5-methylthiothiophene-2-carboxamidine;4-{[(3-methylphenyl)sulfonyl]amino}-5-methylthiothiophene-2-carboxamidine;4-{bis[(3-methylphenyl)sulfonyl]amino}-5-methylthiothiophene-2-carboxamidine;4-{[(4-methylphenyl)sulfonyl]amino}-5-methylthiothiophene-2-carboxamidine;4-{bis[(4-methylphenyl)sulfonyl]amino}-5-methylthiothiophene-2-carboxamidine;5-methylthio-4-{[benzylsulfonyl]amino}-thiophene-2-carboxamidine;4-{[(4-methoxyphenyl)sulfonyl]amino}-5-methylthiothiophene-2-carboxamidine;4-{bis[(4-methoxyphenyl)sulfonyl]amino}-5-methylthiothiophene-2-carboxamidine;4-{[(4-iodophenyl)sulfonyl]amino}-5-methylthiothiophene-2-carboxamidine;4-{[(3,4-dimethoxyphenyl)sulfonyl]amino}-5-methylthiothiophene-2-carboxamidine;4-{bis[(3,4-dimethoxyphenyl)sulfonyl]amino}-5-methylthiothiophene-2-carboxamidine;4-{[(2-chlorophenyl)sulfonyl]amino}-5-methylthiothiophene-2-carboxamidine;4-{[(3-chlorophenyl)sulfonyl]amino}-5-methylthiothiophene-2-carboxamidine;4-{bis[(3-chlorophenyl)sulfonyl]amino}-5-methylthiothiophene-2-carboxamidine;4-{[(4-chlorophenyl)sulfonyl]amino}-5-methylthiothiophene-2-carboxamidine;4-{bis[(4-chlorophenyl)sulfonyl]amino}-5-methylthiothiophene-2-carboxamidine;5-methylthio-4-[(phenylsulfonyl)amino]thiophene-2-carboxamidine;4[bis(phenylsulfonyl)amino]-5-methylthiophene-2-carboxamidine;4-({[4-tert-butyl)phenyl]sulfonyl}amino)-5-methylthiothiophene-2-carboxamidine;4-(bis{[4-tert-butyl)phenyl]sulfonyl}amino)-5-methylthiothiophene-2-carboxamidine;4-{[((1E)-2-phenylvinyl)sulfonyl]amino}-5-methylthiothiophene-2-carboxamidine;5-methylthio-4-({[4-(phenylsulfonyl)(2-thienyl)sulfonyl}amino)thiophene-2-carboxamidine;or pharmaceutically acceptable salts or prodrugs thereof.
 3. A methodaccording to claim 1, wherein the optional substituents on the aromaticring of any group containing an optionally substituted aromatic ring isselected from halogen, C₁₋₆alkyl, C₁₋₆alkoxy, hydroxy, nitro,trifluoromethyl, optionally substituted C₆₋₁₀aryl, optionallysubstituted C₆₋₁₀aryloxy, optionally substituted C₆₋₁₀arylmethoxy,C₁₋₆aminoalkyl, carboxy, 3,4-methylenedioxy, 3,4-ethylenedioxy,3,4-propylenedioxy, amino, mono- or di-(C₁₋₆)alkylamino, mono- ordi-C₆₋₁₀arylamino, C₆₋₁₀alkylsulfonylamino, C₆₋₁₀arylsulfonylamino,C₁₋₈arcylamino, C₁₋₈alkoxycarbonyl, C₁₋₆alkanoylamino, C₆₋₁₄aroylamino,C₁₋₆hydroxyalkyl, methylsulfonyl, phenylsulfonyl, optionally substitutedthienyl and tetrazolyl.
 4. A method according to claim 1 wherein R² isC₁₋₆ alkylsulfonylamino, C₆₋₁₀ar(C₁₋₆)alkylsulfonylamino,C₆₋₁₀ar(C₂₋₆)alkenylsulfonylamino, C₆₋₁₀arylsulfonylamino,heteroarylsulfonylamino, di(C₆₋₁₀ar(C₁₋₆)alkylsulfonyl)amino,di(C₆₋₁₀ar(C₂₋₆)alkenylsulfonyl)amino, di(C₆₋₁₀arylsulfonyl)amino, ordi-(heteroarylsulfonyl)amino, wherein any of the aryl or heteroarylcontaining groups are optionally substituted on the aromatic ring.
 5. Amethod according to claim 4, wherein R² is C₆₋₁₀arylsulfonylamino,di-(C₆₋₁₀arylsulfonyl)amino, C₆₋₁₀ar(C₁₋₃)alkylsulfonylamino,di-(C₆₋₁₀ar(C₁₋₃)alkylsulfonyl)amino, or thienylsulfonylamino, any ofwhich is optionally substituted on the aromatic ring.
 6. A methodaccording to claim 1, wherein R² is biphenylsulfonylamino,bis(biphenylsulfonyl)amino, naphth-2-ylsulfonylamino,di(naphth-2-ylsulfonyl)amino, 6-bromonaphth-2-ylsulfonylamino,di(6-bromonaphth-2-ylsulfonyl)amino, naphth-1-ylsulfonylamino,di(naphth-1-ylsulfonyl)amino, 2-methylphenylsulfonylamino,di-(2-methylphenylsulfonyl)amino, 3-methylphenylsulfonylamino,di-(3-methylphenylsulfonyl)amino, 4-methylphenylsulfonylamino,di-(4-methylphenylsulfonyl)amino, benzylsulfonylamino,4-methoxyphenylsulfonylamino, di-(4-methoxyphenylsulfonyl)amino,4-iodophenylsulfonylamino, di-(4-iodophenylsulfonyl)amino,3,4-dimethoxyphenylsulfonylamino,bis-(3,4-dimethoxyphenylsulfonyl)amino, 2-chlorophenylsulfonylamino,di-(2-chlorophenylsulfonyl)amino, 3-chlorophenylsulfonylamino,di-(3-chlorophenylsulfonyl)amino, 4-chlorophenylsulfonylamino,di-(4-chlorophenylsulfonyl)amino, phenylsulfonylamino,di-(phenylsulfonyl)amino, 4-tert-butylphenylsulfonylamino,di-(4-tert-butylphenylsulfonyl)amino, 2-phenylethenylsulfonylamino, or4-(phenylsulfonyl)thien-2-ylsulfonylamino.
 7. A method according toclaim 7, wherein R² is amino, mono(C₁₋₆)alkylamino, di(C₁₋₆)alkylamino,mono(C₆₋₁₀)arylamino, di(C₆₋₁₀)arylamino,mono(C₁₋₆)alkylmono(C₆₋₁₀)arylamino, monoar(C₁₋₆)alkylamino,di(C₆₋₁₀)ar(C₁₋₆)alkylamino, mono(C₁₋₆)alkylmono(C₆₋₁₀)(C₁₋₆)aralkylamino, (C₁₋₆)armonoheteroarylamino, diheteroarylamino, ormono(C₁₋₆)alkylmonoheteroarylamino, wherein any of the aryl orheteroaryl containing groups are optionally substituted on the aromaticring.
 8. A method according to claim 7, wherein R² ismono(C₆₋₁₀)arylamino, mono(C₁₋₆)alkylmono(C₆₋₁₀)arylamino,mono(C₆₋₁₀)ar(C₁₃)alkylamino,mono(C₁₋₆)alkylmono(C₆₋₁₀)ar(C₁₋₃)alkylamino, monoheteroarylamino, ormono(C₁₋₆)alkylmonoheteroarylamino.
 9. A method according to claim 1,wherein R² is anilino, naphtha-2-ylamino, naphtha-1-ylamino,4-(biphenyl)thiazol-2-ylamino, 4-(phenyl)thiazol-2-ylamino,4-phenyl-5-methylthiazol-2-ylamino,4-hydroxy-4-trifluoromethylthiazol-2-ylamino, 3-phenylphenylamino,pyrimidin-2-ylamino, 4-isopropylphenylamino, 3-isopropylphenylamino,4-phenylphenylamino, 3-fluoro-4-phenylphenylamino,3,4-methylenedioxyphenylamino, n-butylphenylamino,N-methyl-N-(2-methylphenyl)amino, 3-nitrophenylamino,4-methoxyphenylamino, 3-methoxyphenylamino, 2-methoxyphenylamino,2-methylphenylamino, 3-methylphenylamino, 3,4-dimethylphenylamino,3-chlorophenylamino, 4-chlorophenylamino,4-(3-fluoro-4-methylphenyl)amino, 4-(indan-5-yl)amino, benzylamino,indanylmethylamino, 2,3-dihydrobenzofuranylmethyl,2-phenylimidazol-5-yl, 3-hydroxybenzyl, 3-phenoxyphenylamino,4-phenoxyphenylamino, 3-benzyloxyphenylamino, 4-benzyloxyphenylamino,quinolin-6-ylamino, quinolin-3-ylamino, 4-(phenylamino)phenylamino,4-(4-ethylphenyl)phenylamino, 4-(dimethylamino)phenylamino,4-cyclohexylphenylamino, 4-(9-ethylcarbazol-3-yl)amino,4-(t-butyl)phenylamino, or 4-methylthiophenyl amino.
 10. A methodaccording to claim 1, wherein R² is alkanoylamino, alkenoylamino,aroylamino, aralkanoylamino, aralkenoylamino, heteroaroylamino, orheteroarylalkanoylamino, any of which is optionally substituted on thearyl or heteroaryl moiety.
 11. A method according to claim 10, whereinR² is (C₆₋₁₀arylcarbonylamino, C₆₋₁₀ar(C₁₋₃)alkylcarbonylamino,C₆₋₁₀ar(C₂₋₃)alkenylcarbonylamino, C₆₋₁₀aryloxy(C₁₋₃)alkylcarbonylamino,C₃₋₈cycloalkylcarbonylamino, C₁₋₆alkylcarbonylamino, orheteroarylcarbonylamino.
 12. A method according to claim 11, wherein R²is 3-hydroxyphenylcarbonylamino, 2-phenylethenylcarbonylamino,phenylcarbonylamino, cyclohexylcarbonylamino,4-methyl-3-nitrophenylcarbonylamino, furan-2-ylcarbonylamino,tert-butylcarbonylamino, 5-(3,5-dichlorophenoxy)furan-2-ylcarbonylamino,naphth-1-ylcarbonylamino, quinolin-2-ylcarbonylamino,4-ethoxyphenylcarbonylamino, phenoxymethylcarbonylamino, or3-methylphenylcarbonylamino.
 13. A method according to claim 1, whereinsaid effective amount is between about 0.01 and about 50 milligrams perkilogram per day.
 14. A method according to claim 13, wherein saideffective amount is between about 0.1 and 20 milligrams per kilogram perday.
 15. A method according to claim 1, wherein said patient has adisease resulting from thrombolytic therapy.
 16. A method according toclaim 1, wherein said patient has a disease resulting from percutaneoustransluminal coronary angioplasty.
 17. A method according to claim 1,wherein said patient has a disease resulting from hip replacement.
 18. Amethod according to claim 1, wherein said patient has a diseaseresulting from coronary bypass.
 19. A method according to claim 1,wherein said patient has deep vein thrombosis.
 20. A method according toclaim 1, wherein said patient has disseminated intravascularcoagulopathy which occurs during septic shock.
 21. A method according toclaim 1, wherein said patient has a viral infection.
 22. A methodaccording to claim 1, wherein said patient has cancer.
 23. A methodaccording to claim 1, wherein said patient has myocardial infarction.24. A method according to claim 1, wherein said patient has had astroke.
 25. A method according to claim 1, wherein said patient hasfibrin formation in the eye.
 26. A method according to claim 1, whereinsaid patient has retinopathy.
 27. A method according to claim 1, whereinsaid patient has adult respiratory distress syndrome.
 28. A methodaccording to claim 1, wherein said patient has inflammation.
 29. Amethod according to claim 1, wherein said patient is wounded.
 30. Amethod according to claim 1, wherein said patient has reperfusiondamage.
 31. A method according to claim 1, wherein said patient hasatherosclerosis.
 32. A method according to claim 1, wherein said patienthas restenosis following balloon angioplasty, atherectomy or arterialstent replacement.
 33. A method according to claim 1, wherein saidpatient is in need of regulating the promotion of neointimal formation.34. A method according to claim 1, wherein said patient is in need ofregulating extracellular matrix proteolysis.
 35. A method according toclaim 1, wherein said patient is in need of regulating tissueremodeling.
 36. A method according to claim 1, wherein said patient isin need of regulating cell migration.